Trivalent NDV-HXP-S vaccine protects against phylogenetically distant SARS-CoV-2 variants of concern in mice (preprint)

Equitable access to vaccines is necessary to limit the global impact of the coronavirus disease 2019 (COVID-19) pandemic and the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. In previous studies, we described the development of a low-cost vaccine based on a Newcastle Disease virus (NDV) expressing the prefusion stabilized spike protein from SARS-CoV-2, named NDV-HXP-S. Here, we present the development of next-generation NDV-HXP-S variant vaccines, which express the stabilized spike protein of the Beta, Gamma and Delta variants of concerns (VOC). Combinations of variant vaccines in bivalent, trivalent and tetravalent formulations were tested for immunogenicity and protection in mice. We show that the trivalent preparation, composed of the ancestral Wuhan, Beta and Delta vaccines, substantially increases the levels of protection and of cross-neutralizing antibodies against mismatched, phylogenetically distant variants, including the currently circulating Omicron variant.

Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants (preprint)

The continual emergence of SARS-CoV-2 variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant, has rendered ineffective a number of previously EUA approved SARS-CoV-2 neutralizing antibody therapies. Furthermore, even those approved antibodies with neutralizing activity against Omicron are reportedly ineffective against the subset of Omicron variants that contain a R346K substitution, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. Following a campaign of antibody discovery based on the vaccination of Harbour H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of Spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against the Omicron and Omicron + R346K variants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for use in human clinical trials.

Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomised, Placebo-Controlled, Phase 1/2 Trial (preprint)

Summary Background Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It’s being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg±CpG1018 (a toll-like receptor 9 agonist), 3 µg±CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov ( NCT04764422 ). Findings Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation’s immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 IU/mL (1 µg, 95% CI 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥4-fold increase over baseline. Interpretation NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2. Funding National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA)

Early Detection of COVID-19 Epidemic Using Search Engine Query Data (preprint)

Background: Early warnings of emerging infectious disease are crucial to prevent epidemics. However, in the early stage of the COVID-19 pandemic, traditional infectious disease surveillance failed to deliver a warning alert. The aim of this work is to develop search-engine-based surveillance methods for the early warning and prediction of COVID-19 outbreaks. Methods: By using more than 444 million Baidu search queries from China as training set, we collected 32 keywords from the Baidu Search Index that may related to COVID-19 outbreak from 18 December 2019 to 11 February 2020. The Beijing Xinfadi outbreak from 30 May 2020 to 30 July 2020 was used as independent test set. A multiple linear regression was applied to model the relationship between the daily query frequencies of keywords and the daily new cases. Findings: Our results show that 11 keywords in search queries were highly correlated to the daily numbers of confirmed cases (r =0.96, P <0.01). An abnormal initial peak (1.46 times the normal volume) in queries appeared on 31 December 2019, which could have served as an early warning signal for an outbreak. Of particular concern, on this day, the volume of the query “Wuhan Seafood Market” increased by over 240 times (from 10 to 2410), the volume of the query “Wuhan outbreak” increased by over 622 times (from 7 to 4359), and 17.5% of China’s query volume originated from Hubei Province, 51.15% of which was from Wuhan city. The quantitative model using four keywords (“Epidemic”, “Masks”, “Coronavirus” and “Clustered pneumonia”) successfully predicted the daily numbers of cases for the next two days, and detected an early signal during the Beijing Xinfadi outbreak (R2 =0.80). Interpretation: Our study demonstrates the ability of search engine query data to detect COVID-19 outbreaks, and suggests that abnormalities in query volume can serve as early warning signals.

A Newcastle disease virus-vector expressing a prefusion-stabilized spike protein of SARS-CoV-2 induces protective immune responses against prototype virus and variants of concern in mice and hamsters (preprint)

Rapid development of coronavirus disease 2019 (COVID-19) vaccines and expedited authorization for use and approval has been proven beneficial to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread and given hope in this desperate situation. It is believed that sufficient supplies and equitable allocations of vaccines are necessary to limit the global impact of the COVID-19 pandemic and the emergence of additional variants of concern. We have developed a COVID-19 vaccine based on Newcastle disease virus (NDV) that can be manufactured at high yields in embryonated eggs. Here we provide evidence that the NDV vector expressing an optimized spike antigen (NDV-HXP-S), upgraded from our previous construct, is a versatile vaccine that can be used live or inactivated to induce strong antibody responses and to also cross-neutralize variants of concern. The immunity conferred by NDV-HXP-S effectively counteracts SARS-CoV-2 infection in mice and hamsters. It is noteworthy that vaccine lots produced by existing egg-based influenza virus vaccine manufacturers in Vietnam, Thailand and Brazil exhibited excellent immunogenicity and efficacy in hamsters, demonstrating that NDV-HXP-S vaccines can be quickly produced at large-scale to meet global demands.

A Newcastle disease virus-vector expressing a prefusion-stabilized spike protein of SARS-CoV-2 induces protective immune responses against prototype virus and variants of concern in mice and hamsters (preprint)

Rapid development of coronavirus disease 2019 (COVID-19) vaccines and expedited authorization for use and approval has been proven beneficial to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread and given hope in this desperate situation. It is believed that sufficient supplies and equitable allocations of vaccines are necessary to limit the global impact of the COVID-19 pandemic and the emergence of additional variants of concern. We have developed a COVID-19 vaccine based on Newcastle disease virus (NDV) that can be manufactured at high yields in embryonated eggs. Here we provide evidence that the NDV vector expressing an optimized spike antigen (NDV-HXP-S), upgraded from our previous construct, is a versatile vaccine that can be used live or inactivated to induce strong antibody responses and to also cross-neutralize variants of concern. The immunity conferred by NDV-HXP-S effectively counteracts SARS-CoV-2 infection in mice and hamsters. It is noteworthy that vaccine lots produced by existing egg-based influenza virus vaccine manufacturers in Vietnam, Thailand and Brazil exhibited excellent immunogenicity and efficacy in hamsters, demonstrating that NDV-HXP-S vaccines can be quickly produced at large-scale to meet global demands.

A follow-up study shows no new infections caused by patients with repeat positive of COVID-19 in Wuhan (preprint)

BackgroundIt has been reported that a few recovered COVID-19 patients could suffer repeat positive, testing positive for the SARS-CoV-2 virus again after they were discharged from hospital. Understanding the epidemiological characteristics of patients with repeat positive is vital in preventing a second wave of COVID-19. MethodsIn this study, the epidemiological and clinical features for 20,280 COVID-19 patients from multiple centers between 31 December 2019 and 4 August 2020 in Wuhan were collected and followed. In addition, the RT-qPCR testing results for 4,079 individuals who had close contact with the patients suffering repeat positive were also obtained. Results2,466 (12.16%) of 20,280 patients presented with a repeat positive of SARS-CoV-2 after they were discharged from hospital. 4,079 individuals had close contact with them. The PCR result were negative for the 4,079 individuals. ConclusionsBy a follow-up study in Wuhan, we show the basic characteristics of patients with repeat positive and no new infections caused by patients with repeat positive of COVID-19.

A Newcastle disease virus (NDV) expressing membrane-anchored spike as a cost-effective inactivated SARS-CoV-2 vaccine (preprint)

A successful SARS-CoV-2 vaccine must be not only safe and protective but must also meet the demand on a global scale at low cost. Using the current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent COVID-19 vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections or significantly attenuated SARS-CoV-2 induced disease. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.

Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as vaccine candidate (preprint)

Due to the lack of protective immunity of humans towards the newly emerged SARS-CoV-2, this virus has caused a massive pandemic across the world resulting in hundreds of thousands of deaths. Thus, a vaccine is urgently needed to contain the spread of the virus. Here, we describe Newcastle disease virus (NDV) vector vaccines expressing the spike protein of SARS-CoV-2 in its wild type or a pre-fusion membrane anchored format. All described NDV vector vaccines grow to high titers in embryonated chicken eggs. In a proof of principle mouse study, we report that the NDV vector vaccines elicit high levels of antibodies that are neutralizing when the vaccine is given intramuscularly. Importantly, these COVID-19 vaccine candidates protect mice from a mouse-adapted SARS-CoV-2 challenge with no detectable viral titer and viral antigen in the lungs. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe spike (S) protein of the SARS-CoV-2 is the major antigen that notably induces neutralizing antibodies to block viral entry. Many COVID-19 vaccines are under development, among them viral vectors expressing the S protein of SARS-CoV-2 exhibit many benefits. Viral vector vaccines have the potential of being used as both live or inactivated vaccines and they can induce Th1 and Th2-based immune responses following different immunization regimens. Additionally, viral vector vaccines can be handled under BSL-2 conditions and they grow to high titers in cell cultures or other species restricted-hosts. For a SARS-CoV-2 vaccine, several viral vectors are being tested, such as adenovirus, measles virus and Modified vaccinia Ankara. Added value of this studyThe NDV vector vaccine against SARS-CoV-2 described in this study has advantages similar to those of other viral vector vaccines. But the NDV vector can be amplified in embryonated chicken eggs, which allows for high yields and low costs per dose. Also, the NDV vector is not a human pathogen, therefore the delivery of the foreign antigen would not be compromised by any pre-existing immunity in humans. Finally, NDV has a very good safety record in humans, as it has been used in many oncolytic virus trials. This study provides an important option for a cost-effective SARS-CoV-2 vaccine. Implications of all the available evidenceThis study informs of the value of a viral vector vaccine against SARS-CoV-2. Specifically, for this NDV based SARS-CoV-2 vaccine, the existing egg-based influenza virus vaccine manufactures in the U.S. and worldwide would have the capacity to rapidly produce hundreds of millions of doses to mitigate the consequences of the ongoing COVID-19 pandemic.

Risk of COVID-19 is associated with long-term exposure to air pollution (preprint)

High risk of severe disease of COVID-19 has been associated with patients with chronic obstructive pulmonary disease, cardiovascular disease or hypertension, and long-term exposure to PM2.5 has been associated with COVID-19 mortality. We collate individual level data of confirmed COVID-19 cases during the first wave of the epidemic in mainland China by March 6, 2020. We pair these data with a mobile phone dataset, covering human movements from Wuhan before the travel ban and inner-city movements during the time of emergency response from 324 cities in China. Adjusting for socio-economic factors, an increase of 10 g/m3 in NO2 or PM2.5 was found to be associated with a 22.41% (95%CI: 7.28%-39.89%) or 15.35% (95%CI: 5.60%-25.98%) increase in the number of COVID-19 cases, and a 19.20% (95%CI: 4.03%-36.59%) or 9.61% (95%CI: 0.12%-20.01%) increase in severe infection, respectively. Our results highlight the importance of air quality improvements to health benefits.

Early evaluation of the Wuhan City travel restrictions in response to the 2019 novel coronavirus outbreak (preprint)

Respiratory illness caused by a novel coronavirus (COVID-19) appeared in China during December 2019. Attempting to contain infection, China banned travel to and from Wuhan city on 23 January and implemented a national emergency response. Here we evaluate the spread and control of the epidemic based on a unique synthesis of data including case reports, human movement and public health interventions. The Wuhan shutdown slowed the dispersal of infection to other cities by an estimated 2.91 days (95%CI: 2.54-3.29), delaying epidemic growth elsewhere in China. Other cities that implemented control measures pre-emptively reported 33.3% (11.1-44.4%) fewer cases in the first week of their outbreaks (13.0; 7.1-18.8) compared with cities that started control later (20.6; 14.5-26.8). Among interventions investigated here, the most effective were suspending intra-city public transport, closing entertainment venues and banning public gatherings. The national emergency response delayed the growth and limited the size of the COVID-19 epidemic and, by 19 February (day 50), had averted hundreds of thousands of cases across China.