Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. At this time, trial data was lacking, and we addressed this in a study of UK healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a sub-study of 589 individuals, we show that this single dose induces SARS-CoV-2 neutralizing antibody (NAb) responses and a sustained B and T cell response to spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by enrichment of CD4 + T cells expressing IL2. Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol.

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.

41In December 2019 an outbreak of coronavirus disease emerged in 42 Wuhan, China. The causative agent was subsequently identified and named severe 43 acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which rapidly spread 44 worldwide causing a pandemic. Currently there are no licensed vaccines or 45 therapeutics available against SARS-CoV-2 but numerous candidate vaccines are in 46 development and repurposed drugs are being tested in the clinic. There is a vital need 47 for authentic COVID-19 animal models to further our understanding of pathogenesis 48 and viral spread in addition to pre-clinical evaluation of candidate interventions. 49 50Here we report a dose titration study of SARS-CoV-2 to determine the most suitable 51 infectious dose to use in the ferret model. We show that a high (5x10 6 pfu) and medium 52 (5x10 4 pfu) dose of SARS-CoV-2 induces consistent upper respiratory tract (URT) viral 53 RNA shedding in both groups of six challenged animals, whilst a low dose (5x10 2 pfu) 54 resulted in only one of six displaying signs of URT viral RNA replication. The URT 55 shedding lasted up to 21 days in the high dose animals with intermittent positive signal 56 from day 14. Sequential culls revealed distinct pathological signs of mild multifocal 57 bronchopneumonia in approximately 5-15% of the lung, observed on day 3 in high and 58 medium dosed animals, with presence of mild broncho-interstitial pneumonia on day 59 7 onwards. No obvious elevated temperature or signs of coughing or dyspnoea were 60 observed although animals did present with a consistent post-viral fatigue lasting from 61 day 9-14 in the medium and high dose groups. After virus shedding ceased, re-62 challenged ferrets were shown to be fully protected from acute lung pathology. The 63Page 4 of 39 endpoints of URT viral RNA replication in addition to distinct lung pathology and post 64 viral fatigue were observed most consistently in the high dose group. This ferret model 65 of SARS-CoV-2 infection presents a mild clinical disease (as displayed by 80% of 66 patients infected with SARS-CoV-2). In addition, intermittent viral shedding on days 67 14-21 parallel observations reported in a minority of clinical cases. 68 69 70 71 Word count: 327 72 Introduction 73 74 Coronaviruses are positive sense, single stranded RNA viruses belonging to the family 75 Coronaviridae 1 . These viruses can infect a range of animals, including humans and 76 usually cause a mild respiratory infection, much like the common cold. Two highly 77 pathogenic coronaviruses have emerged in the human population in the last 20 years; 78 severe acute respiratory syndrome (SARS) CoV and middle eastern respiratory 79 syndrome (MERS) CoV. SARS-CoV infected approximately 8,000 people worldwide with 80 a case fatality rate (CFR) of 10%, while MERS-CoV has infected approximately 2,500 81 people with a CFR of 36% 2 .82 83 In December 2019 several pneumonia cases of unknown cause emerged in Wuhan, 84 Hubei, China. Deep sequencing analysis from lower respiratory tract samples from ...

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The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.

The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.

Background People with HIV on antiretroviral therapy with good CD4 T cell counts make effective immune responses following vaccination against SARS-CoV-2. There are few data on longer term responses and the impact of a booster dose. Methods Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed twelve months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µl. Immune responses to the ancestral strain and variants of concern were measured by anti-spike IgG ELISA, MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, Activation Induced Marker (AIM) assay and T cell proliferation. Findings 54 participants received two doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) one year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titres (MSD), ACE-2 inhibition and IgG ELISA results were significantly higher compared to Day 182 titres (P < 0.0001 for all three). SARS-CoV-2 specific CD4+ T cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4 + and CD8+ T cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. Conclusions In PWH receiving a third vaccine dose, there were significant increases in B and T cell immunity, including to known VOCs.