ABSTRACT
The continuing emergence of immune evasive SARS-CoV-2 variants and the previous SARS-CoV-1 outbreak have accentuated the need for broadly protective sarbecovirus vaccines. Targeting the conserved S2-subunit of SARS-CoV-2 is a particularly promising approach to elicit broad protection. Here, expanding on our previous work with S2-based vaccines, we developed a nanoparticle vaccine displaying multiple copies of the SARS-CoV-1 S2 subunit. This vaccine alone, or as a cocktail with a SARS-CoV-2 S2 subunit vaccine, protected transgenic K18-hACE2 mice from challenges with Omicron subvariant XBB as well as several sarbecoviruses identified as having pandemic potential including the bat sarbecovirus WIV1, BANAL-236, and a pangolin sarbecovirus. Challenge studies in Fc-g receptor knockout mice revealed that antibody-based cellular effector mechanisms played a role in protection elicited by these vaccines. These results demonstrate that our S2-based vaccines provide broad protection against clade 1 sarbecoviruses and offer insight into the mechanistic basis for protection.
ABSTRACT
New Zealand (NZ)’s elimination of community transmission of influenza and respiratory syncytial virus (RSV) infections in May 2020, due to stringent COVID-19 countermeasures, provided a rare opportunity to assess the impact of border restrictions and relaxations on common respiratory viral infections over the subsequent two-years. Using multiple surveillance systems, we observed that border closure to most non-residents, and mandatory government-managed isolation and quarantine on arrival for those allowed to enter, appeared to be effective in keeping influenza and RSV infections out of the NZ community. Partial border relaxations through quarantine free travel with Australia and other countries were associated, within weeks, with importation of RSV and influenza into NZ in 2021 and 2022. Border restrictions did not have effect on community transmission of other respiratory viruses such as rhinovirus and parainfluenza virus type 1. These data can inform future pandemic influenza preparedness as well as provide insights into effective strategies to plan and model the impact of seasonal influenza, RSV, and other respiratory viral infections.
Subject(s)
COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Tract InfectionsABSTRACT
Remote simulation in education predates the COVID-19 pandemic, and its more widespread contemporary use can help inform future teaching practices. This article outlines the development of a remote-facilitated mental simulation (RFMS) delivered to second-year paramedic science students at a UK university. This was created using Sprick et al's simulation design model: preparation, briefing, simulation activity, debriefing, reflection and evaluation. Mental simulation is a teaching modality where participants mentally rehearse processes rather than practical skills. Speaking thoughts aloud helps learners to reflect on their thought processes and decision-making. While studies on remote simulation involve a facilitator viewing participants interacting with a simulation, in this study the participants were observers and the facilitator interacted with the simulation equipment. This arrangement may increase access to simulation for learners who do not have access to such facilities. Participants were engaged through group activities and psychological fidelity was maintained by providing real-time streaming of patient observations. The RFMS was evaluated positively by respondents.
ABSTRACT
Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.
Subject(s)
COVID-19 , Ossification of Posterior Longitudinal Ligament , Inflammation , Pleural DiseasesABSTRACT
Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.
Subject(s)
COVID-19ABSTRACT
The need for SARS-CoV-2 next-generation vaccines has been highlighted by the rise of variants of concern (VoC) and the long-term threat of emerging coronaviruses. Here, we designed and characterized four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of prefusion SARS-CoV-2 Spike (S), S1 and RBD. These immunogens induced robust S-binding, ACE2-inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A Spike-ferritin nanoparticle (SpFN) vaccine elicited neutralizing titers (ID50 > 10,000), 20-fold greater than convalescent donor serum titers following a single immunization, while RBD-Ferritin nanoparticle (RFN) immunogens elicited similar responses after two immunizations, that also showed potent neutralization against circulating variants of concern. Passive transfer of IgG purified from SpFN- or RFN-immunized mice protected K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicited ACE2 blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1 highlighting the broad response elicited by these immunogens.Funding: We acknowledge support from the U.S. Department of Defense, Defense Health Agency (Restoral FY20). This work was also partially executed through a cooperative agreement between the U.S. Department of Defense and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (W81XWH-18-2- 0040).Declaration of Interest: M.G.J. and K.M. are named as inventors on International Patent Application No. WO/2021/21405 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on International Patent Application No. WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion Coronavirus Spike Proteins and Their Use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M are named inventors on “Compositions And Methods For Vaccine Delivery”, US Patent Application: 16/607,917. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R., P.M.M., and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Zoltan Beck is currently employed at Pfizer.Ethical Approval: All research in this study involving animals was conducted in compliance with the Animal Welfare Act, and other federal statutes and regulations relating to animals and experiments involving animals and adhered to the principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. The research protocol was approved by the Institutional Animal Care and Use Committee of WRAIR. BALB/c and C57BL/6 mice were obtained from Jackson Laboratories (Bar Harbor, ME).
Subject(s)
Coronavirus InfectionsABSTRACT
Background: Household transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly contributes to increased community cases. Methods: We conducted a prospective case-ascertained study to investigate the household secondary attack rate (SAR) and contributing factors in urban Los Angeles, California, USA. Household members were enrolled prospectively if ≥1 member tested positive for SARS-CoV-2 by polymerase chain reaction (PCR). Nasopharyngeal swabs for PCR and symptom data were obtained over multiple longitudinal visits. Serology was obtained at enrollment. Findings: A total of 489 individuals in 105 households were enrolled from June to December 2020. The mean household SAR was 77.7% (95%CI: 71.4-84.0). A third (32.1%) of index cases were asymptomatic. High SAR was associated with both symptomatic and asymptomatic index cases (76.4% [95%CI: 68.8-83.9%] vs. 79.7% [95% CI: 66.2-93.3%], p=0.66). The most common age for index cases was children <18 years old during low community transmission periods and adults ≥18 years old during peak community transmission (p=0.003). Children and adults index cases both efficiently transmitted SARS-CoV-2 within households (SAR 74.0% [95%CI: 63.4-84.6%] vs. 81.3% [95%CI: 72.3-90.3%], p=0.49). Hispanic/Latinx ethnicity was significantly associated with higher SAR in the multivariable analysis of household factors (p= 0.030). Interpretation: The SAR in our urban setting with large ethnic minority populations is much higher than previously described. SAR was disproportionately and significantly impacted by Hispanic/Latinx ethnicity. Asymptomatic individuals and children play important roles as index cases. Future vaccination and public health efforts need special focus on these groups to help mitigate SARS-CoV-2 spread.Funding: NIH/NIAID U01AI144616-02S1, Open PhilanthropyDeclaration of Interests: PSP has received consultant fees from Sanofi-Pasteur and Seqirus. She also receives research funding from AstraZeneca for an unrelated study. AG has received consultant fees from Janssen. All other authors have no conflicts of interest to report.Ethics Approval Statement: The study was approved by the Institutional Review Board at Children’sHospital Los Angeles.
Subject(s)
Coronavirus InfectionsABSTRACT
Background: There is an urgent need to rapidly distinguish Covid-19 from other respiratory conditions, including influenza, at first-presentation. Point-of-care tests not requiring laboratory-support will speed diagnosis and protect health-care staff. We studied the feasibility of using breath-analysis to distinguish these conditions with near-patient gas chromatography-ion mobility spectrometry (GC-IMS).Methods: Independent studies at Edinburgh, UK, and Dortmund, Germany, recruited adult patients with possible Covid-19 at hospital presentation. Participants gave a single breath-sample for volatile organic compounds analysis by GC-IMS. Covid-19 infection was identified by RT-qPCR of oral/nasal swabs together with clinical-review. Following correction for environmental contaminants, potential Covid-19 breath-biomarkers were identified by multi-variate analysis and comparison to GC-IMS databases. A Covid-19 breath-score based on the relative abundance of a panel of volatile organic compounds was proposed and tested against the cohort data.Findings: Ninety-eight patients were recruited, of whom 21/33 (63.6%) and 10/65 (15.4%) had Covid-19 in Edinburgh and Dortmund, respectively. Other diagnoses included asthma, COPD, bacterial pneumonia, and cardiac conditions. Multivariate analysis identified aldehydes (ethanal, octanal), ketones (acetone, butanone), and methanol that discriminated Covid-19 from other conditions. An unidentified-feature with significant predictive power for severity/death was isolated in Edinburgh, while heptanal was identified in Dortmund. Differentiation of patients with definite diagnosis (25 and 65) of Covid-19 from non-Covid-19 was possible with 80% and 81.5% accuracy in Edinburgh and Dortmund respectively (sensitivity/specificity 82.4%/75%; area-under-the-receiver-operator-characteristic [AUROC] 0.87 95% CI 0.67 to 1) and Dortmund (sensitivity/ specificity 90%/80%; AUROC 0.91 95% CI 0.87 to 1).Interpretation: These two studies independently indicate that patients with Covid-19 can be rapidly distinguished from patients with other conditions at first healthcare contact. The identity of the marker compounds is consistent with Covid-19 derangement of breath-biochemistry by ketosis, gastrointestinal effects, and inflammatory processes. Development and validation of this approach may allow rapid diagnosis of Covid-19 in the coming endemic flu seasons.Funding Statement: MR was supported by an NHS Research Scotland Career Researcher Clinician award. DMR was supported by the University of Edinburgh ref COV_29Declaration of Interests: The authors have nothing to declare.Ethics Approval Statement: Two independent studies were set up in the emergency departments of the Royal Infirmary of Edinburgh (RIE, Institutional Review Board ref RIE, 20/SS/0042), UK, and Klinikum Dortmund (KD, Institutional Review Board ref IfADo 176/2020), Germany.