ABSTRACT
The efficacy of vaccines targeting SARS-CoV-2 is becoming apparent now that the mRNA and adenovirus vector vaccines that have been approved for emergency use are showing promise. However, the longevity of the protective immune response and its efficacy against emerging variants remains to be determined. To improve longevity and future protection against variants, we have designed a DNA vaccine encoding both the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) and its nucleocapsid (N) protein, the latter of which is highly conserved amongst beta coronaviruses. The vaccine elicits strong pro-inflammatory CD4 Th1 and CD8 T-cell responses to both proteins, with these responses being significantly enhanced by fusing the nucleocapsid sequence to a modified Fc domain. We have shown that the vaccine also stimulates high titre antibody responses to RBD which efficiently neutralise in both a pseudotype and live virus neutralisation assay and show cross reactivity with S proteins from the emerging variants Alpha (B.1.1.7) and Beta (B.1.351). This DNA platform can be easily adapted to target variant RBD and N proteins and we show that a vaccine variant encoding the B.1.351 RBD sequence stimulates cross-reactive humoral and T-cell immunity. These data support the translation of this DNA vaccine platform into the clinic, thereby offering a particular advantage for targeting emerging SARS-CoV-2 variants.
ABSTRACT
ObjectiveTo assess the incidence of symptomatic and asymptomatic SARS-CoV-2 seropositivity in healthcare workers and subsequent transmission to their close contacts within their household. To assess changes in immunoglobulin (Ig) and neutralising antibodies (nAbs) in exposed participants. SettingTwo acute National Health Service (NHS) hospitals within the East Midlands region of England. BackgroundThe UK has been one of the most severely affected countries during the COVID-19 pandemic. Transmission from healthcare workers to the wider community is a potential major vector for spread of SARS-CoV-2 which is not well described in the current literature. MethodsHealthcare workers (HCW) were recruited from two Hospitals within the East Midlands of England and underwent serial blood sampling for anti-SARS-CoV-2 antibodies (both nucleocapsid and spike protein for IgG, IgM and IgA) between 20 April and 30 July 2020, with the presence of neutralising antibodies (nAbs) assessed for positive participants. Cohabitees of the volunteers were invited to attend testing in July -August 2020 and underwent identical serological testing as the HCWs. Results633 healthcare professionals were recruited. 178 household contacts of 137 professionals volunteered for the study. 18% of healthcare professionals (115 out of 633) tested as seropositive during the study period, compared to an estimated seroprevalence of 7% within the general population. The rate of symptomatic COVID-19 was 27.5% compared to an asymptomatic rate of 15.1%. Rates of positivity declined across the study period for all immunoglobulins (overall positivity from 16.7% to 6.9%). 7.2% of the cohabitees tested as seropositive. 58 cohabitees lived with a serologically positive HCW; this group had a seropositive rate of 15.5%, compared to 2.5% of cohabitees without a seropositive HCW, a six-fold increase in risk (Odds ratio 7.16 95% CI 1.86 to 27.59), p = 0.0025). Given the observed decay rates and data from Public Health England, we estimate that the proportion of seropositive cohabitees living with a seropositive HCW at the height of the first wave could have been as high as 44%. 110 out of 115 (95.7%) HCWs and 12 out of 13 (92.3%) cohabitees who tested positive developed detectable nAbs. 56.5% (65 out of 115) of SARS-CoV-2 positive HCWs developed a neutralising titre with an IC50[≥]1/300; no cohabitee achieved this level.. ConclusionsTransmission of SARS-CoV-2 between healthcare professionals and their home contacts appears to be a significant factor of viral transmission, but, even accounting for the decline in seropositivity over time, less than 44% of adult cohabitees of seropositive healthcare workers became seropositive. Routine screening and priority vaccination of both healthcare professionals and their close contacts should be implemented to reduce viral transmission from hospitals to the community. SUMMARY BOXESO_ST_ABSSection 1: What is already known on this topicC_ST_ABSO_LIHealthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population due, at least in part, to high levels of occupational exposure. C_LIO_LIIgA, IgM and IgG are detectable for most patients after 11 days post SARS-CoV-2 infection but all decline in the weeks following SAR-CoV-2 exposure. C_LIO_LIRates of transmission to healthcare workers, and therefore subsequent transmission to their close contacts, may be reduced with effective PPE. C_LI Section 2: What this study addsO_LIThe amount of neutralising antibodies formed may be dependent on IgG response as it is much lower among seropositive cohabitees than seropositive healthcare workers. C_LIO_LINHS Healthcare workers had a far greater seroprevalence of SARS-CoV-2 infection compared to the general population. C_LIO_LICohabitees of positive healthcare workers have a 6-fold increased risk of developing serological evidence of SARS-CoV-2 infection compared to the general population. C_LIO_LIDespite this increased risk, transmission at home is less than 50% even from highly exposed healthcare workers, but remains an important potential vector of transmission from hospitals to the wider community. C_LI Research into contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles published between January 1 2020 and January 27, 2021 with the terms "Covid-19", "healthcare workers", and "transmission" "home {NOT nursing} or household". We did not restrict our search by language or type of publication. We identified 38 studies of which only one assessed the prevalence among HCW households using Canadian national databases. Our PubMed search yielded only one serological study within the German Healthcare system, which suggested very low transmission from healthcare workers to their close cohabitees. Added value of this studyTo our knowledge, this is the largest longitudinal serological cohort study assessing transmission of SARS-CoV-2 infection from the UK healthcare environment to the home (n = 633 healthcare workers, 178 cohabitees). Our findings showed that serological evidence within the HCW was high with 18% of healthcare professionals (115 out of 633) tested as seropositive during the study period, compared to an estimated seroprevalence of 7% within the general population. A cohabitee of a seropositive HCW had a six-fold increase of being seropositive themselves compared to a baseline rate of 2.5%. Despite this increased risk, transmission at home is less than 50% even from highly exposed healthcare workers, but remains an important potential vector of transmission from hospitals to the wider community. Rates of positivity declined across the study period for all immunoglobulins (overall positivity from 16.7% to 6.9%). Given the observed decay rates and data from Public Health England, we estimate that the proportion of seropositive cohabitees living with a seropositive HCW at the height of the first wave could have been as high as 44%. Implications of all available evidenceUnderstanding the transmission during the first wave from the healthcare setting into the home and the extent of such transmissions is essential to understand containment strategies of novel SARS-CoV-2 variants or to understand viral transmission of future respiratory viruses. NHS workers appeared to be at an increased risk of contracting of SARS-CoV-2 infection compared to the HCWs of other nations; we hypothesise that this may be related to a scarcity of appropriate personal protective equipment during the initial wave of SARS-CoV-2. Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. An infected HCW, whether symptomatic or not, appears to be a significant bridge for transmission of SARS-CoV-2 to their close home contacts.
ABSTRACT
The COVID-19 pandemic caused by the emergent SARS-CoV-2 coronavirus threatens global public health and there is an urgent need to develop safe and effective vaccines. Here we report the generation and the preclinical evaluation of a novel replication-defective gorilla adenovirus-vectored vaccine encoding the pre-fusion stabilized Spike (S) protein of SARS-CoV2. We show that our vaccine candidate, GRAd- COV2, is highly immunogenic both in mice and macaques, eliciting both functional antibodies which neutralize SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and a robust, Th1- dominated cellular response in the periphery and in the lung. We show here that the pre-fusion stabilized Spike antigen is superior to the wild type in inducing ACE2-interfering, SARS-CoV2 neutralizing antibodies. To face the unprecedented need for vaccine manufacturing at massive scale, different GRAd genome deletions were compared to select the vector backbone showing the highest productivity in stirred tank bioreactors. This preliminary dataset identified GRAd-COV2 as a potential COVID-19 vaccine candidate, supporting the translation of GRAd-COV2 vaccine in a currently ongoing Phase I clinical trial (NCT04528641).
ABSTRACT
COVID-19 continues to cause a pandemic, having infected more than 20 million people globally. Successful elimination of the SARS-CoV-2 virus will require an effective vaccine. However, the immune correlates of infection are currently poorly understood. While neutralizing antibodies are believed to be essential for protection against infection, the contribution of the neutralizing antibody response to resolution of SARS-CoV-2 infection has not yet been defined. In this study the antibody responses to the SARS-CoV-2 spike protein and nucleocapsid proteins were investigated in a UK patient cohort, using optimised immunoassays and a retrovirus-based pseudotype entry assay. It was discovered that in severe COVID-19 infections an early antibody response to both antigens was associated with improved prognosis of infection. While not all SARS-CoV-2-reactive sera were found to possess neutralizing antibodies, neutralizing potency of sera was found to be greater in patients who went on to resolve infection, compared with those that died from COVID-19. Furthermore, viral genetic variation in spike protein was found to influence the production of neutralizing antibodies. Infection with the recently described spike protein variant 614G produced higher levels of neutralizing antibodies when compared to viruses possessing the 614D variant. These findings support the assertion that vaccines targeting generation of neutralizing antibodies may be useful at limiting SARS-CoV-2 infection. Assessment of the antibody responses to SARS-CoV-2 at time of diagnosis will be a useful addition to the diagnostic toolkit, enabling stratification of clinical intervention for severe COVID-19 disease.
