ABSTRACT
Duration of protection from SARS-CoV-2 infection in people with HIV (PWH) following vaccination is unclear. In a sub-study of the phase 2/3 the COV002 trial (NCT04400838), 54 HIV positive male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells >350 cells/ul) received two doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and MesoScale Discovery (MSD)), neutralisation, ACE-2 inhibition, gamma interferon ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that 6 months after vaccination the majority of measurable immune responses were greater than pre-vaccination baseline, but with evidence of a decline in both humoral and cell mediated immunity. There was, however, no significant difference compared to a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although were lower than wild type. Pre-existing cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater post-vaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the on-going policy to vaccinate PWH against SARS-CoV-2, and underpin the need for long-term monitoring of responses after vaccination.
ABSTRACT
Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of COVID. However, this agent carries a black box warning for infection complications, which may include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), or worsening of hepatitis C virus (HCV). Due to the pace of clinical research during the COVID pandemic, prospective evaluation of these risks has not been possible. We undertook a systematic review, generating mean cumulative incidence estimates for reactivation of HBV and TB at 3.3% and 4.3%. We could not generate estimates for HCV. These data derive from heterogeneous studies pre-dating the COVID outbreak, with differing epidemiology and varied approaches to screening and prophylaxis. We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm for clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID. KEY POINTSUse of tocilizumab treatment in COVID-19 may risk infective complications. We have undertaken a systematic literature review to assess the risks of reactivation of HBV and TB, generating mean estimates of 3.3% and 4.3% incidence, respectively.
ABSTRACT
A major issue in identification of protective T cell responses against SARS-CoV-2 lies in distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity generated by exposure to other coronaviruses. We characterised SARS-CoV-2 T cell immune responses in 168 PCR-confirmed SARS-CoV-2 infected subjects and 118 seronegative subjects without known SARS-CoV-2 exposure using a range of T cell assays that differentially capture immune cell function. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) were found in those who had been infected by SARS-CoV-2 but were rare in pre-pandemic and unexposed seronegative subjects. However, seronegative doctors with high occupational exposure and recent COVID-19 compatible illness showed patterns of T cell responses characteristic of infection, indicating that these readouts are highly sensitive. By contrast, over 90% of convalescent or unexposed people showed proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on the choice of assay and antigen. Memory responses to specific non-spike proteins provides a method to distinguish recent infection from pre-existing immunity in exposed populations.
ABSTRACT
Extensive global sampling and whole genome sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to characterise its spread, and to identify mutations that may increase transmission or enable the virus to escape therapies or vaccines. Two important components of viral spread are how frequently variants arise within individuals, and how likely they are to be transmitted. Here, we characterise the within-host diversity of SARS-CoV-2, and the extent to which genetic diversity is transmitted, by quantifying variant frequencies in 1390 clinical samples from the UK, many from individuals in known epidemiological clusters. We show that SARS-CoV-2 infections are characterised by low levels of within-host diversity across the entire viral genome, with evidence of strong evolutionary constraint in Spike, a key target of vaccines and antibody-based therapies. Although within-host variants can be observed in multiple individuals in the same phylogenetic or epidemiological cluster, highly infectious individuals with high viral load carry only a limited repertoire of viral diversity. Most viral variants are either lost, or occasionally fixed, at the point of transmission, consistent with a narrow transmission bottleneck. These results suggest potential vaccine-escape mutations are likely to be rare in infectious individuals. Nonetheless, we identified Spike variants present in multiple individuals that may affect receptor binding or neutralisation by antibodies. Since the fitness advantage of escape mutations in highly-vaccinated populations is likely to be substantial, resulting in rapid spread if and when they do emerge, these findings underline the need for continued vigilance and monitoring.
ABSTRACT
The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally. ACE2 is a receptor for SARS-CoV-2 and differences in expression may affect susceptibility to COVID-19. Using HCV-infected liver tissue from 195 individuals, we discovered that among genes negatively correlated with ACE2, interferon signalling pathways were highly enriched and observed down-regulation of ACE2 after interferon-alpha treatment. Negative correlation was also found in the gastrointestinal tract and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of ACE2 across tissue and species. Performing a genome-wide eQTL analysis, we discovered that polymorphisms in the interferon lambda (IFNL) region are associated with ACE2 expression. Increased ACE2 expression in the liver was also associated with age and presence of cirrhosis. Polymorphisms in the IFNL region may impact not only antiviral responses but also ACE2 with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.
