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The Oxford Vaccine Group is an independent multi-disciplinary clinical trials and epidemiology group based at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford. OVG works towards the goal of developing new and improved vaccines for the prevention of infection in adults and children.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial
BACKGROUND: Older adults (aged >/=70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged >/=65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2.2 x 10(10) virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3.5-6.5 x 10(10) virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-gamma enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged >/=56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and >/=70 years 17 561 AU/mL [9705-37 796], n=47; p=0.68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and >/=70 years, 161 [73-323], n=47; p=0.40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and >/=70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
An exploratory analysis of the response to ChAdOx1 nCoV-19 (AZD1222) vaccine in males and females.
BACKGROUND: There are known differences in vaccine reactogenicity and immunogenicity by sex. Females have been shown to report greater reactogenicity and generate higher humoral and cellular immune responses than males following vaccination with several different vaccines. Whether this is also the case for COVID-19 vaccines is currently unknown, as COVID-19 vaccine study data disaggregated by sex are not routinely reported. Therefore, we have assessed the influence of sex on reactogenicity, immunogenicity and efficacy of COVID-19 vaccine ChAdOx1 nCoV-19. METHODS: Vaccine efficacy was assessed in 15169 volunteers enrolled into single-blind randomised controlled trials of ChAdOx1 nCoV-19 in Brazil and the UK, with the primary endpoint defined as nucleic acid amplification test (NAAT)-positive symptomatic SARS-CoV-2 infection. All participants were electronically randomised to receive two standard doses of vaccine or the control product. Logistic regression models were fitted to explore the effect of age and sex on reactogenicity, and linear models fitted to log-transformed values for immunogenicity data. Reactogenicity data were taken from self-reported diaries of 788 trial participants. Pseudovirus neutralisation assay data were available from 748 participants and anti-SARS-CoV-2 spike IgG assay data from 1543 participants. FINDINGS: 7619 participants received ChAdOx1 nCoV-19 and 7550 received the control. Vaccine efficacy in participants after two doses of ChAdOx1 nCoV-19 (4243 females and 3376 males) was 66.1% (95% CI 55.9-73.9%) in males and 59.9% (95% CI 49.8-67.9%) in females; with no evidence of a difference in efficacy between the sexes (vaccine by sex interaction term P=0.3359). A small, statistically significant difference in anti-spike IgG was observed (adjusted GMR 1.14; 95% CI 1.04-1.26), with higher titres in females than males, but there were no statistically significant differences in other immunological endpoints. Whilst the majority of individuals reported at least one systemic reaction following a first dose of ChAdOx1 nCoV-19, females were twice as likely as males to report any systemic reaction after a first dose (OR 1.95; 95% CI 1.37-2.77). Measured fever of 38°C or above was reported in 5% of females and 1% of males following first doses. Headache and fatigue were the most commonly reported reactions in both sexes. INTERPRETATION: Our results show that there is no evidence of difference in efficacy of the COVID-19 vaccine ChAdOx1 nCoV-19 in males and females. Greater reactogenicity in females was not associated with any difference in vaccine efficacy. FUNDING: Studies were registered with ISRCTN 90906759 (COV002) and ISRCTN 89951424 (COV003) and follow-up is ongoing. Funding was received from the UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil, and AstraZeneca.
Durability of ChAdOx1 nCoV-19 vaccination in people living with HIV.
Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/μL) received 2 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 Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ 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 prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.
Implementation and adherence to regular asymptomatic testing in a COVID-19 vaccine trial.
BACKGROUND: For pathogens which cause infections that present asymptomatically, evaluating vaccine efficacy (VE) against asymptomatic infection is important for understanding a vaccine's potential epidemiological impact. Regular testing for subclinical infections is a potentially valuable strategy but its success hinges on participant adherence and minimising false positives. This paper describes the implementation and adherence to weekly testing in a COVID-19 vaccine trial. METHODS: COV002 was a phase 2/3 trial assessing the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Asymptomatic infections were detected using weekly self-administered swabs for RT-PCR testing. We analysed adherence using mixed-effects regression models and estimated the probability of true and false positive asymptomatic infections using estimates of adherence and testing characteristics. FINDINGS: 356,551 tests were self-administered by 10,811 participants during the 13-month follow-up. Median adherence was 75.0% (IQR 42·6-90·9), which translated to a 74·5% (IQR 50·9-78·8) probability of detecting a positive asymptomatic infection during the swabbing period, and between 21 and 96 false positives during VE evaluation. The odds of returning a swab declined by 8% per week and further after testing positive and unblinding. Adherence was higher in older age groups, females and non-healthcare workers. INTERPRETATION: The COV002 trial demonstrated the feasibility of running a long-term regular asymptomatic testing strategy. This information could be valuable for designing future phase III vaccine trials in which infection is an outcome. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, AstraZeneca.
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
Age differences in immunity to human seasonal coronaviruses and the immunogenicity of ChAdOx1 nCoV-19 (AZD1222).
BACKGROUND: ChAdOx1 nCoV-19 (AZD1222) vaccine was widely deployed to protect against severe COVID-19 in adults, but the relationship between pre-existing immunity to human seasonal coronaviruses (HCoVs) and vaccine-induced SARS-CoV-2 (SCoV2) response across age groups remains unclear. METHODS: We analysed SCoV2 and HCoVs antibody profiles in UK volunteers (aged 6-≥70), assessing antibody levels, avidity, and FcγR binding after receiving one or two doses of ChAdOx1 nCoV-19. Adult cohorts from trials in Brazil and Kenya were also included to evaluate geographical impacts on baseline HCoVs and SCoV2 induced response. FINDINGS: In the UK cohort, younger individuals had higher SCoV2 IgG, avidity, FcγR binding and cross-reactivity, particularly towards OC43 and HKU1. The greatest differences were seen after the first dose of ChAdOx1 nCoV-19, but these effects diminished after the second dose. Although baseline HCoVs IgG varied geographically, similar trends were observed across adult cohorts with younger adults showing higher SCoV2 IgG compared to older adults (UK and Brazil). INTERPRETATION: These findings contribute to a better understanding of the immunogenicity of ChAdOx1-based vaccines in various age groups. Determining whether this applies across other vaccines using same platform is essential for evaluating the viability of one-dose regimens in outbreak responses. FUNDING: The clinical trials COV002, COV003, COV004, and COV006 were made possible by funding from Astra Zeneca, the NIHR and the University of Oxford, UK Department of Health and Social Care, through the UK National Institute for Health and Care Research, the Wellcome Trust (220991), and Innovate UK (project 971614).