Innate immune sensing of self-derived double-stranded RNA by RIG-I-MAVS-TNF-α regulates the survival and senescence fate of SARS-2-S syncytia (preprint)

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an important health threat. Syncytial formation by infected cells mediated by the SARS-CoV-2 spike protein (SARS-2-S) is a hallmark of COVID-19-associated pathology. Although SARS-CoV-2 infection evokes cellular senescence, as in other viruses, the direct link between SARS-2-S-induced syncytia with senescence in the absence of viral infection and their senescence fate determinants remain unknown. Here, we show that syncytia formed by cells expressing exogenously delivered SARS-2-S exhibited a senescence-like phenotype in vitro and that SARS-2-S mRNA induced senescence phenotype in vivo. Extracellular vesicles (EVs) containing SARS-2-S also induced senescent syncytium formation independent of the de novo synthesis of SARS-2-S. Mechanistically, we show that the accumulation of endogenous dsRNA, partially that whose formation is induced by activation of the unfolded protein response (UPR), in SARS-2-S syncytia triggers RIG-I-MAVS signalling to drive the TNF-α-dependent survival and senescence fate of SARS-2-S syncytia. Our findings suggest that the fusogenic ability of SARS-2-S might contribute to the side effects of particular COVID-19 vaccines or perhaps long COVID-19 syndrome and provide insight into how these effects can be prevented.

Impact of various vaccine boosters on neutralization against Omicron following prime vaccinations with inactivated or adenovirus-vectored vaccine (preprint)

Since the first report on November 24, 2021, the Omicron SARS-CoV-2 variant is now overwhelmingly spreading across the world. Two SARS-CoV-2 inactivated vaccines (IAVs), one recombinant protein subunit vaccine (PRV), and one adenovirus-vectored vaccine (AdV) have been widely administrated in many countries including China to pursue herd immunity. Here we investigated cross-neutralizing activities in 341 human serum specimens elicited by full-course vaccinations with IAV, PRV and AdV, and by various vaccine boosters following prime IAV and AdV vaccinations. We found that all types of vaccines induced significantly lower neutralizing antibody titers against the Omicron variant than against the prototype strain. For prime vaccinations with IAV and AdV, heterologous boosters with AdV and PRV, respectively, elevated serum Omicron-neutralizing activities to the highest degrees. In a mouse model, we further demonstrated that among a series of variant-derived RBD-encoding mRNA vaccine boosters, it is only the Omicron booster that significantly enhanced Omicron neutralizing antibody titers compared with the prototype booster following a prime immunization with a prototype S-encoding mRNA vaccine candidate. In summary, our systematical investigations of various vaccine boosters inform potential booster administrations in the future to combat the Omicron variant.

Dynamical analysis of the SIS epidemic model in cluster events

Considering individuals’ aggregation behavior, we study the SIS (Susceptible-Infected-Susceptible) epidemic model in a modified activity driven network (ADN). The relations among individuals are divided into three categories: strong links (SLs), the first kind of weak links (FWLs) and the second kind of weak links (SWLs). Based on the mean field approximation, we theoretically calculate the epidemic threshold condition while the strong links structure is a homogeneous or a heterogeneous network, respectively. Finally, we provide some numerical examples that support our theoretical results.

Willingness to Receive COVID-19 Vaccination Among People Living With HIV and AIDS in China: A Nationwide Online Survey (preprint)

Background: People living with HIV and AIDS (PLWHA) could benefit from COVID-19 vaccination. There is a dearth of evidence on willingness to receive COVID-19 vaccination (WTR) among PLWHA.Methods: The study is a multicenter cross-sectional online survey conducted in eight conveniently selected Chinese metropolitan cities between January and February 2021. Participants were PLWHA aged 18-65 years and living in the study cities. Eight community-based organizations (CBO) providing services to PLWHA, one in each city, facilitated the recruitment through their networks. Eligible PLWHA completed an online survey developed using Golden Data, a widely used encrypted web-based survey platform in China. Logistic regression models and path analysis were used in data analysis.Findings: Out of 10,845 PLWHA approached by the CBO, 2740 completed the survey. This analysis was performed among 2570 participants who had never received COVID-19 vaccination. Over half of the participants reported WTR (57·2%, 1470/2570). After adjusting for potential confounders, all four constructs of the Theory of Planned Behavior (TPB) were significantly associated with WTR, including positive attitudes (adjusted odds ratio, aOR: 1·11, 95%CI: 1·09, 1·12), negative attitudes (aOR: 0·96, 95%CI: 0·94, 0.97), perceived support from significant others (perceived subjective norm) (aOR: 1·53, 95%CI: 1·46, 1·61), and perceived higher behavioral control (aOR: 1·13, 95%CI: 1·11, 1·14). At the interpersonal level, receiving advice supportive of COVID-19 vaccination from doctors (aOR: 1·99, 95%CI: 1·65, 2·40), CBO staff (aOR: 1·89, 95%CI: 1·51, 2·36), friends and/or family members (aOR: 3·22, 95%CI: 1·93, 5·35), and PLWHA peers (aOR: 2.38, 95%CI: 1·85, 3·08) were associated with higher WTR. Overall opinion supporting COVID-19 vaccination for PLWHA on Internet or social media was also positively associated with WTR (aOR: 1·59, 95%CI: 1·31, 1·94). Path analysis indicated that interpersonal-level variables was indirectly associated with WTR through TPB-related perceptions (β=0·43, 95% CI=0·37, 0·51).Interpretation: PLWHA in China reported a relatively low WTR. Interpersonal communication and Internet/social media may be the major sources to convey information and promote COVID-19 vaccination in the population.Funding Statement: This work was supported by the Academic technology leader project of Changzhi Medical College (Grant No. XSQ201902), he Beijing Excellent Talent Plan (2018000021223ZK04) and the National Institute of Mental Health of the National Institutes of Health under Award Numbers R34MH119963.Declaration of Interests: The authors have no conflicts of interest to disclose.Ethics Approval Statement: The Institutional Review Boards of Changzhi Medical College (RT2021003) approved this study.

Medication Non-Adherence and Condomless Anal Intercourse Increased Substantially During the COVID-19 Pandemic Among MSM PrEP Users: A Observational Longitudinal Study in Four Chinese Metropolises (preprint)

Background:  The coronavirus disease (COVID-19) pandemic has impacted HIV prevention strategies globally. However, changes in pre-exposure prophylaxis (PrEP) adherence and HIV-related behaviors, and their associations with medication adherence among MSM PrEP users remains unclear since the onset of the COVID-19 pandemic.  Methods:  A longitudinal observational study of HIV-negative MSM PrEP users was conducted in four Chinese metropolises from February to March 2020, assessing the changes in PrEP adherence and HIV-related behaviours before and during the COVID-19. The primary outcome was poor PrEP adherence determined from self-reported missing at least one PrEP dose in the previous month. We used mulitivariable logistic regression to determine factors correlated with poor adherence during the COVID-19. Findings:  We enrolled 791 eligible participants (418 [52·8%] in daily PrEP, 373 [47·2%] in event-driven PrEP). Compared with the data conducted before the COVID-19, the proportion of PrEP users decreased from 97·9% to 64·3%, and the proportion of poor PrEP adherence increased from 23.6% to 50·1% during the COVID-19 (odds ratio [OR] 3·24, 95% confidence interval (CI) 2·61–4·02). While the percentage of condomless anal intercourse (CAI) with regular partners (11·8% vs 25·7%) and with casual partners (4·4% vs 9·0%) both significantly increased. The proportion of those who were tested for HIV decreased from 50·1% to 25·9%. Factors correlated with poor PrEP adherence during the COVID-19 included not being tested for HIV (adjusted odds ratio [aOR]=1·38 [95% CI: 1·00, 1·91]), using condoms consistently with regular partners (vs. never, aOR=2·19 [95% CI: 1·16, 4·13]) and being married or cohabitating with a woman (vs. not married, aOR=3·08 [95% CI: 1·60, 5·95]). Interpretation:  Increased poor PrEP adherence and CAI along with the decrease in HIV testing can lead to increases in HIV acquisition and of drug resistance to PrEP. Targeted interventions are needed to improve PrEP adherence and HIV prevention strategies. Trial Registration: Chinese Clinical Trial Registry (ChiCTR-IIN-17013762). Funding Statement: The Mega-Projects of national science research for the13th Five-Year Plan (2017ZX10201101), the National Natural Science Foundation of China (81872674), and the National Science and Technology Major Project (2018ZX10101001-001-003). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This study was reviewed and approved by the Medical Science Research Ethics Committee of the First Affiliated Hospital of China Medical University ([2018]2015-139-5).

A single dose of an adenovirus-vectored vaccine provides complete protection of the upper and lower respiratory tracts against SARS-CoV-2 challenge (preprint)

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we found that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protected mice completely against SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protected ferrets from SARS-CoV-2 infection in the upper respiratory tract. This study suggested that a combination of intramuscular and mucosal vaccination maybe provide a desirable protective efficacy and different Ad5-nCoV delivery modes are worth further investigation in human clinical trials.

A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability (preprint)

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.