Non-hospitalised, vaccinated adults with COVID-19 caused by Omicron BA.1 and BA.2 present with changing symptom profiles compared to those with Delta despite similar viral kinetics

IntroductionThe impact of COVID-19 vaccination on disease in the community has been limited, as a result of both SARS-CoV-2 Variants of Concern that partially escape vaccine-induced immunity. We sought to characterise symptoms and viral loads over the course of COVID-19 infection in otherwise-healthy vaccinated adults, representative of the general population, to assess whether current self-isolation guidance remains justified. MethodsIn a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive PCR or lateral flow test, self-swabbed on alternate days until day 10. We compared symptoms and viral kinetics between infections caused by VOCs Delta and Omicron (sub-variants BA.1 and BA.2) and investigated applicability of UK NHS isolation guidelines to these newer VOCs. Results373 infection episodes were reported among 349 participants. Across VOCs, symptom duration was similar, however symptom profiles differed significantly among infections caused by Delta, Omicron BA.1 and BA.2. Anosmia was reported in <10% of participants with BA.1 and BA.2, compared to 42% with Delta infection, coryza fatigue and myalgia predominated. Most notably, viral load trajectories and peaks did not differ between Delta, BA.1 and BA.2, irrespective of symptom severity, VOC or vaccination status. ConclusionCOVID-19 isolation guidance should not differ based on symptom severity or febrile illness and must remain under review as new SARS-CoV-2 VOCs emerge and population immunity changes. Our study emphasises the ongoing transmission risk of Omicron sub-variants in vaccinated adults with mild symptoms that may extend beyond current isolation periods. summaryWe provide prospective characterisation of COVID-19 caused by Delta and Omicron BA.1 and BA.2 in healthy, vaccinated adults. A minority of adults report symptoms that would mandate self-isolation, despite having equally high viral shedding across VOCs that persisted beyond ten days.

Broad human and animal coronavirus neutralisation by SARS-CoV-2 S2-targeted vaccination

Several common-cold coronaviruses (HCoVs) are endemic in humans and several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current Coronavirus disease 2019 (COVID-19) pandemic. Whilst antibody cross-reactivity with the Spike glycoproteins (S) of diverse coronaviruses has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to or mediate protection, when induced naturally or through vaccination. Using a mouse model, we show that prior HCoV-OC43 S immunity primes neutralising antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, mouse vaccination with SARS-CoV-2 S2 elicits antibodies that neutralise diverse animal and human alphacoronaviruses and betacoronaviruses in vitro, and protects against SARS-CoV-2 challenge in vivo. Lastly, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induces stronger and broader neutralising antibody response than booster Wuhan S vaccination, suggesting it may prevent repertoire focusing caused by repeated homologous vaccination. The data presented here establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern (VOCs), as well as to unpredictable, yet inevitable future coronavirus zoonoses.

Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains

We examined the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.7 that arose in the United Kingdom and spread globally. Antibodies elicited by B.1.1.7 infection exhibited significantly reduced recognition and neutralisation of parental strains or of the South Africa B.1.351 variant, than of the infecting variant. The drop in cross-reactivity was more pronounced following B.1.1.7 than parental strain infection, indicating asymmetric heterotypic immunity induced by SARS-CoV-2 variants.

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study

There is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+ T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.

Standard operating procedures for SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay

The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 40,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated standard operating procedure (SOP) for high-throughput SARS-CoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive.

SARS-CoV-2 virus and antibodies in front-line Health Care Workers in an acute hospital in London: preliminary results from a longitudinal study

BackgroundAlthough SARS-CoV-2 infection in Healthcare Workers (HCWs) is a public health concern, there is little description of their longitudinal antibody response in the presence or absence of SARS-CoV-2 and symptoms. We followed HCWs in an acute London hospital to measure seroconversion and RNA detection at the peak of the pandemic. MethodsWe enrolled 200 patient-facing HCWs between 26 March and 8 April 2020 and collected twice-weekly self-administered nose and throat swabs, symptom data and monthly blood samples. Swabs were tested for SARS-CoV-2 by PCR, and serum for antibodies to spike protein by ELISA and flow cytometry. FindingsDuring the first month, 42/200 (21%) HCWs were PCR positive in at least one nose and throat swab. Only 8/42 HCW (19%) who were PCR positive during the study period had symptoms that met current case definition. Of 181 HCWs who provided enrollment and follow-up blood samples, 82/181 (45.3%) were seropositive. In 33 HCWs who had positive serology at baseline but were PCR negative, 32 remained PCR negative. One HCW had a PCR positive swab six days after enrollment, likely representing waning infection. ConclusionThe high seropositivity and RNA detection in these front-line HCWs brings policies to protect staff and patients into acute focus. Our findings have implications for planning for the second wave and for vaccination campaigns in similar settings. The evidence of asymptomatic SARS-CoV-2 infection indicates that asymptomatic HCW surveillance is essential, while our study sets the foundations to answer pertinent questions around the duration of protective immune response and the risk of re-infection.

Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans

Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections1. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19), is a recent zoonotic infection that has quickly reached pandemic proportions2,3. Zoonotic introduction of novel coronaviruses is thought to occur in the absence of pre-existing immunity in the target human population. Using diverse assays for detection of antibodies reactive with the SARS-CoV-2 spike (S) glycoprotein, we demonstrate the presence of pre-existing humoral immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. These were predominantly of the IgG class and targeted the S2 subunit. In contrast, SARS-CoV-2 infection induced higher titres of SARS-CoV-2 S-reactive IgG antibodies, targeting both the S1 and S2 subunits, as well as concomitant IgM and IgA antibodies, lasting throughout the observation period of 6 weeks since symptoms onset. SARS-CoV-2-uninfected donor sera also variably reacted with SARS-CoV-2 S and nucleoprotein (N), but not with the S1 subunit or the receptor binding domain (RBD) of S on standard enzyme immunoassays. Notably, SARS-CoV-2-uninfected donor sera exhibited specific neutralising activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes, according to levels of SARS-CoV-2 S-binding IgG and with efficiencies comparable to those of COVID-19 patient sera. Distinguishing pre-existing and de novo antibody responses to SARS-CoV-2 will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

Scalable and Resilient SARS-CoV2 testing in an Academic Centre

The emergence of the novel coronavirus SARS-CoV-2 has led to a pandemic infecting more than two million people worldwide in less than four months, posing a major threat to healthcare systems. This is compounded by the shortage of available tests causing numerous healthcare workers to unnecessarily self-isolate. We provide a roadmap instructing how a research institute can be repurposed in the midst of this crisis, in collaboration with partner hospitals and an established diagnostic laboratory, harnessing existing expertise in virus handling, robotics, PCR, and data science to derive a rapid, high throughput diagnostic testing pipeline for detecting SARS-CoV-2 in patients with suspected COVID-19. The pipeline is used to detect SARS-CoV-2 from combined nose-throat swabs and endotracheal secretions/ bronchoalveolar lavage fluid. Notably, it relies on a series of in-house buffers for virus inactivation and the extraction of viral RNA, thereby reducing the dependency on commercial suppliers at times of global shortage. We use a commercial RT-PCR assay, from BGI, and results are reported with a bespoke online web application that integrates with the healthcare digital system. This strategy facilitates the remote reporting of thousands of samples a day with a turnaround time of under 24 hours, universally applicable to laboratories worldwide.