Efficacy of ChAdOx1 vaccines against SARS-CoV-2 Variants of Concern Beta, Delta and Omicron in the Syrian hamster model (preprint)

ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirus–vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 was shown to have 74% vaccine efficacy (VE) against symptomatic disease in clinical trials and over 2.5 billion doses of vaccine have been released for worldwide use. However, SARS-CoV-2 continues to circulate and consequently, variants of concern (VoCs) have been detected, with substitutions in the S protein that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial over boosting with vaccines encoding the ancestral S protein, even though current real-world data is suggesting good efficacy against hospitalization and death following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluated the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. We then investigated the efficacy of a single dose of AZD2816 or AZD1222 against the Omicron VoC. As seen previously, minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 5 days post inoculation, in contrast to lungs of control animals. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.

Tolerability and Immunogenicity After a Late Second Dose or a Third Dose of ChAdOx1 nCoV-19 (AZD1222) (preprint)

Background: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between first and second dose extends. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose, the immunity after an extended interval between the first and second dose of ChAdOx1 nCoV-19(AZD1222), and the response to a third dose as a late booster. Methods: Volunteers aged 18-55 years who were enrolled in a Phase 1/2 or Phase 2/3 clinical trial of ChAdOx1 nCoV-19 and had received either a single dose or two doses of 5×10 10 viral particles were invited back for vaccination. Reactogenicity and immunogenicity of a delayed second dose or a third dose are reported here.Findings: Antibody titres after a single dose and measured on d362 remain higher than the titres measured on d0 (62.61 EU; 95% CI 47.43-82.64 vs 1 EU 95% CI 1-16). 30 participants received a late second dose of ChAdOx1 nCoV-19 (median 44 weeks after first dose), antibody titres were higher in those with a longer interval between first and second dose (median EU for 8-12, 15-25, and 44-46 weeks were 923 [IQR 525-1764], 1860 [IQR 917-4934] and 3738 [IQR 1824-6625] respectively). 90 participants received a third dose and antibody titres were significantly higher following a third dose (FRNT50 612 [IQR 351-920]) when compared with the response 28 days after a second dose (FRNT 50 319 [IQR 176-591]. T-cell responses were also boosted after a third dose. Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.Interpretation: A longer delay before the second dose of ChAdOx1 nCoV-19 leads to an increased antibody titre after the second dose. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlate with high efficacy after second dose and boosts T-cell responses.Funding: UK Research and Innovation (MC_PC_19055), Engineering and Physical Sciences Research Council (EP/R013756/1), National Institute for Health Research (COV19 OxfordVacc-01), Coalition for Epidemic Preparedness Innovations (Outbreak Response To Novel Coronavirus (COVID-19)), National Institute for Health Research Oxford Biomedical Research Centre (BRC4 Vaccines Theme), Thames Valley and South Midland’s NIHR Clinical Research Network, and AstraZeneca. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. SCG and AVSH are cofounders of and shareholders in Vaccitech (collaborators in the early development of this vaccine candidate) and named as inventors on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine (SCG only). TL is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and was a consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AJP is a NIHR Senior Investigator.Ethical Approval: In the UK, the COV001 and COV002 studies were approved by the South Central Berkshire Research Ethics Committee (COV001 reference 20/SC/0145, March 23, 2020; and COV002 reference 20/SC/0179; conditional approval April 8, full approval April 19, 2020).

Divergent trajectories of antiviral memory after SARS-Cov-2 infection (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is normally controlled by effective host immunity including innate, humoral and cellular responses. However, the trajectories and correlates of acquired immunity, and the capacity of memory responses months after infection to neutralise variants of concern - which has important public health implications - is not fully understood. To address this, we studied a cohort of 78 UK healthcare workers who presented in April to June 2020 with symptomatic PCR-confirmed infection or who tested positive during an asymptomatic screening programme and tracked virus-specific B and T cell responses longitudinally at 5-6 time points each over 6 months, prior to vaccination. We observed a highly variable range of responses, some of which - T cell interferon-gamma (IFN-γ) ELISpot, N-specific antibody waned over time across the cohort, while others (spike-specific antibody, B cell memory ELISpot) were stable. In such cohorts, antiviral antibody has been linked to protection against re-infection. We used integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling Over Night) to explore this heterogeneity and to identify predictors of sustained immune responses. Hierarchical clustering defined a group of high and low antibody responders, which showed stability over time regardless of clinical presentation. These antibody responses correlated with IFN-γ ELISpot measures of T cell immunity and represent a subgroup of patients with a robust trajectory for longer term immunity. Importantly, this immune-phenotype associates with higher levels of neutralising antibodies not only against the infecting (Victoria) strain but also against variants B.1.1.7 (alpha) and B.1.351 (beta). Overall memory responses to SARS-CoV-2 show distinct trajectories following early priming, that may define subsequent protection against infection and severe disease from novel variants.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses (preprint)

It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.

Antibody evasion by the Brazilian P.1 strain of SARS-CoV-2 (preprint)

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

Heterologous vaccination regimens with self-amplifying RNA and Adenoviral COVID vaccines induce superior immune responses than single dose vaccine regimens in mice (preprint)

Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two dose heterologous vaccination regimens than single dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine (preprint)

Vaccine development against the SARS-CoV-2 virus focuses on the principal target of the neutralizing immune response, the spike (S) glycoprotein. Adenovirus-vectored vaccines offer an effective platform for the delivery of viral antigen, but it is important for the generation of neutralizing antibodies that they produce appropriately processed and assembled viral antigen that mimics that observed on the SARS-CoV-2 virus. Here, we describe the structure, conformation and glycosylation of the S protein derived from the adenovirus-vectored ChAdOx1 nCoV-19/AZD1222 vaccine. We demonstrate native-like post-translational processing and assembly, and reveal the expression of S proteins on the surface of cells adopting the trimeric prefusion conformation. The data presented here confirms the use of ChAdOx1 adenovirus vectors as a leading platform technology for SARS-CoV-2 vaccines.

A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice (preprint)

The spread of SARS-CoV-2 has caused a global pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection, and may enable the relaxation of social distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection, therefore it is desirable that any new vaccine candidates should elicit a robust immune response in older adults. Here, we test the immunogenicity of the adenoviral vectored vaccine ChAdOx1 nCoV-19 (AZD-1222) in aged mice. We find that a single dose of this vaccine induces cellular and humoral immunity in aged mice, but at a reduced magnitude than in younger adult mice. Furthermore, we report that a second dose enhances the immune response to this vaccine in aged mice, indicating that a primeboost strategy may be a rational approach to enhance immunogenicity in older persons.

Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19 (preprint)

Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.

ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques (preprint)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.