ABSTRACT
As the SARS-CoV-2 virus continues to evolve, novel XBB sub-lineages such as XBB.1.5, XBB.1.16, EG.5, HK.3 (FLip), and XBB.2.3, as well as the most recent BA.2.86, have been identified and aroused global concern. Understanding the efficacy of current vaccines and the immune system's response to these emerging variants is critical for global public health. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, or a booster vaccination of the recently approved tetravalent protein vaccine in China (SCTV01E), or had contracted a breakthrough infection with BA.5/BF.7/XBB virus. Comparative analysis of their neutralization profiles against a broad panel of 30 SARS-CoV-2 sub-lineage viruses revealed that strains such as BQ.1.1, CH.1.1, and all the XBB sub-lineages exhibited heightened resistance to neutralization than previous variants, however, despite the extra mutations carried by emerging XBB sub-lineages and BA.2.86, they did not demonstrate significantly increased resistance to neutralization compared to XBB.1.5. Encouragingly, the SCTV01E booster vaccination consistently induced robust and considerably higher neutralizing titers against all these variants than breakthrough infection did. Cellular immunity assays also showed that the SCTV01E booster vaccination elicited a higher frequency of virus-specific memory B cells but not IFN-{gamma} secreting T cells. Our findings underline the importance of developing novel multivalent vaccines to more effectively combat future viral variants.
Subject(s)
Breakthrough Pain , COVID-19ABSTRACT
The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum neutralizing activity against diverse coronaviruses. Through single B cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, one potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1 and SARS-CoV viral challenge in golden Syrian hamsters, respectively. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.
Subject(s)
Lung Diseases , Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
In this paper, we present a Distributionally Robust Markov Decision Process (DRMDP) approach for addressing the dynamic epidemic control problem. The Susceptible-Exposed-Infectious-Recovered (SEIR) model is widely used to represent the stochastic spread of infectious diseases, such as COVID-19. While Markov Decision Processes (MDP) offers a mathematical framework for identifying optimal actions, such as vaccination and transmission-reducing intervention, to combat disease spreading according to the SEIR model. However, uncertainties in these scenarios demand a more robust approach that is less reliant on error-prone assumptions. The primary objective of our study is to introduce a new DRMDP framework that allows for an ambiguous distribution of transition dynamics. Specifically, we consider the worst-case distribution of these transition probabilities within a decision-dependent ambiguity set. To overcome the computational complexities associated with policy determination, we propose an efficient Real-Time Dynamic Programming (RTDP) algorithm that is capable of computing optimal policies based on the reformulated DRMDP model in an accurate, timely, and scalable manner. Comparative analysis against the classic MDP model demonstrates that the DRMDP achieves a lower proportion of infections and susceptibilities at a reduced cost.
Subject(s)
COVID-19 , Communicable DiseasesABSTRACT
SARS-CoV-2 is continuing to evolve and diversify, with an array of various Omicron sub-lineages, including BA.5, BA.2.75, BN.1, BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5, now circulating globally at recent time. In this study, we evaluated the neutralization sensitivity of a comprehensive panel of Omicron subvariants to sera from different clinical cohorts, including individuals who received homologous or heterologous booster vaccinations, vaccinated people who had Delta or BA.2 breakthrough infection in previous waves, and patients who had BA.5 or BF.7 breakthrough infection in the current wave in China. All the Omicron subvariants exhibited substantial neutralization evasion, with BQ.1, BQ.1.1, XBB.1, and XBB.1.5 being the strongest escaped subvariants. Sera from Omicron breakthrough infection, especially the recent BA.5 or BF.7 breakthrough infection, exhibited higher neutralizing activity against all Omicron sub-lineages, indicating the chance of BA.5 and BF.7 being entirely replaced by BQ or XBB subvariants in China in a short-term might be low. We also demonstrated that the BQ and XBB subvariants were the most resistant viruses to monoclonal antibodies. Continuing to monitor the immune escape of SARS-CoV-2 emerging variants and developing novel broad-spectrum vaccines and antibodies are still crucial.
Subject(s)
Breakthrough PainABSTRACT
Many new Omicron sub-lineages have been reported to evade neutralizing antibody response, including BA.2, BA.2.12.1, BA.4 and BA.5. Most recently, another emerging sub-lineage BA.2.75 has been reported in multiple countries. In this study, we constructed a comprehensive panel of pseudoviruses (PsVs), including wild-type, Delta, BA.1, BA.1.1, BA.2, BA.3, BA.2.3.1, BA.2.10.1, BA.2.12.1, BA.2.13, BA.2.75 and BA.4/BA.5, with accumulate coverage reached 91% according to the proportion of sequences deposited in GISAID database since Jan 1st, 2022. We collected serum samples from healthy adults at day14 post homologous booster with BBIBP-CorV, or heterologous booster with ZF2001, primed with two doses of BBIBP-CorV, or from convalescents immunized with three-dose inactivated vaccines prior to infection with Omicron BA.2, and tested their neutralization activity on this panel of PsVs. Our results demonstrated that all Omicron sub-lineages showed substantial evasion of neutralizing antibodies induced by vaccination and infection, although BA.2.75 accumulated the largest number of mutations in its spike, BA.4 and BA.5 showed the strongest serum escape. However, BA.2 breakthrough infection could remarkably elevated neutralization titers against all different variants, especially titers against BA.2 and its derivative sub-lineages.
ABSTRACT
Background& Aims: The Coronavirus Disease 2019 (COVID-19) has become a global epidemic and has caused a lasting and huge loss of life security, economic development and social stability in more than 180 countries around the world. Unfortunately, there is still no specific treatment for COVID-19 till now, therefore, at this point, all potential therapies need to be critically considered. LL-37 is one of the best-studied human antimicrobial peptide (AMPs) that has a broad-spectrum activity against bacteria and viruses. The use of living, genetically modified organisms (GMOs) is an effective approach for delivery of therapeutic proteins. The aim of this study was to determine the safety and efficacy of the Lactococcus lactis which has been genetically modified to produce the therapeutic human antimicrobial peptide LL-37 (herein after referred to cas001) in the patients of COVID-19. Methods: Firstly we constructed genetically modified food-grade probiotic, Lactococcus lactis, with sequence of seven tandem repeats of mature human LL-37 under control of the nisin-inducible nisA promoter to produce the cas001. A total of 20 healthy SD rats, half male and half female (There were five male and five female in the control group, the same in treatment group) were used to observe the acute toxic reaction and death after daily administration of cas001 for three weeks, which helps to provide necessary reference basis for clinical dose selection, verificaition of toxic reaction and possible target organs. According to the estimated clinical dosage of 1 x 108CFU /kg/day, considering the conversion of body surface area, the dose for rats should be multiplied by 6.17 to 6 x 108 CFU/kg/day. We administrated 100 times higher dose at 6 x 1010 CFU/kg/day to rats. In order to investigate the pharmacokinetics of cas001, male SD rats (body weight 250-300g, 1 x 1010 /animal, n=3) were given oral administration of LL-37 bacteria powder. The concentration of LL-37 in the blood before and after gavage was detected by ELISA kit (Hycult biotechnology Cat# HK321). Human clinical study was approved by Ethics committee of Chinese PLA General Hospital (S2020-074-04) and a total of 11 patients with mild symptoms were enrolled in Wuhan hankou hospital and Huoshenshan hospital. They were enrolled voluntarily and all patients signed informed consent. Among them, there were 5 males and 6 females, aged 55 {+/-} 12 (36-70) years old, and the duration from onset to medication enrollment was 35 {+/-} 19 (5-68) days. 6 patients were nucleic acid positive and 5 patients were nucleic acid negative when they were enrolled. All patients received the oral drug cas001 treatment according to requirement(1 x 109 CFU/capsule, 3 capsules/time, three times a day for 3weeks), with an average follow-up time of 33 {+/-} 15 days (see table 1 for the results). Findings: Western blot analysis shows that reasonable amount of LL-37 were induced by different concentrations of nisin, which means we have successfully constructed cas001. In the pre-clinical safety evaluation test, after three weeks administration of cas001, no adverse effects were observed on the rat's body weight, food and water intake, hematological or serum biochemical parameters. The results showed that the LD50 of cas001 was higher than that of the 100 times of the expected clinical dose of 6 x 1010 CFU/day. These results showed that cas001 could be safe in animal experiments. In addition, rat pharmacokinetics results showed that the serum concentration of LL-37 reached peak 2 hours after gavage of cas001 and returned to basal level 6 hours after gavage. During study period, the volunteers did not feel any discomfort while taking the cas001 capsules, and two hours after oral administration, the concentration of LL-37 were increased in healthy volunteers. cas001 shows definite effect in the improvement of gastrointestinal symptoms and is possible to have effects in improving the systemic symptoms and respiratory symptoms and may play a role in the improvement of results of nucleic acid test and lung CT test. 11 patients enrolled showed good compliance, tolerance, subjective feeling and actively interacted with the doctors. None of the patients had any adverse reactions. Conclusions Based on above observations, we conclude here that as an oral anti-viral agent, cas001 displayed good safety profiles. It is very hard to reach conclusion of clinical outcomes related to the cas001, although changes of several symptoms indicate encouraging findings.