Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2.
Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137,
Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001).
Interpretation ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme.
Our preliminary findings show that the candidate ChAdOx1 nCoV-19 vaccine given as a single dose was safe and tolerated, despite a higher reactogenicity profile than the control vaccine, MenACWY. No serious adverse reactions to ChAdOx1 nCoV-19 occurred. The majority of adverse events reported were mild or moderate in severity, and all were self-limiting. The profile of adverse events reported here is similar to that for other ChAdOx1-vectored vaccines and other closely related simian adenoviruses, such as ChAdOx2, ChAd3, and ChAd63, expressing multiple different antigens at this dose level, as well as to some licensed vaccines. A dose of 5 × 1010 viral particles was chosen on the basis of our previous experience with ChAdOx1 MERS, where despite increased reactogenicity, a dose–response relationship with neutralising antibodies was observed. The protocol was written when the pandemic was accelerating in the UK and a single higher dose was chosen to provide the highest chance of rapid induction of neutralising antibody. In the context of a pandemic wave where a single higher, but more reactogenic, dose might be more likely to rapidly induce protective immunity, the use of prophylactic paracetamol appears to increase tolerability and would reduce confusion with COVID-19 symptoms that might be caused by short-lived vaccine-related symptoms without compromising immunogenicity.
We show that a single dose of ChAdOx1 nCoV-19 elicits an increase in spike-specific antibodies by day 28 and neutralising antibody in all participants after a booster dose. High levels of neutralising antibody at baseline seen in a small number of participants probably indicates prior asymptomatic infection, as potential participants with recent COVID-19-like symptoms or with a history of positive PCR test for SARS-CoV-2 were excluded from the study. Individuals with high titres on the day of vaccination who received ChAdOx1 nCoV-19 were boosted by vaccination.
Neutralising antibodies targeting different epitopes of the spike glycoprotein have been associated with protection from COVID-19 in early preclinical rhesus macaque studies.Although a correlate of protection has not been defined for COVID-19, high levels of neutralising antibodies have been shown in convalescent individuals, with a wide range, as confirmed in our study.Antibodies capable of neutralising live SARS-CoV-2 were induced by day 28 with titres of 51 (PHE MNA80) and 218 (PHE PRNT50), and with titres of 29 (Marburg VN) or 136 (PHE MNA80) after a booster dose, as measured using different assays. In a non-human primate study where primary SARS-CoV-2 infection elicited at least short-term protection against reinfection, neutralising antibody titres of the magnitude found in our study after boosting appeared sufficient to confer protection using the Marburg VN assay methodology.Neutralising antibody titres were increased by a two-dose regimen, and further investigation of this approach is underway. The correlation of neutralisation assays with IgG quantitation indicates that, if confirmed, a standardised ELISA might be sufficient to predict protection, should neutralising antibody also be shown to be protective in humans. We have presented data from three different live neutralising antibody assays and a pseudo-neutralisation assay, which show tight correlation with each other but give very different neutralising antibody titres. This issue highlights the urgent need for centralised laboratory infrastructure to allow bridging between vaccine candidates and accelerate the availability of multiple products to provide the global capacity to end the pandemic. If any one candidate demonstrates efficacy, bridging this result to other candidate vaccines through rigorously conducted laboratory assays will become a crucial issue for global health.
Importantly, there are accumulating data to suggest T-cell responses play an important role in COVID-19 mitigation; individuals who were exposed but asymptomatic developed a robust memory T-cell response without symptomatic disease in the absence of a measurable humoral response. Adenovirus-vectored vaccines are known to induce strong cellular immunity and ChAdOx1 nCoV-19 vaccination resulted in marked increases in SARS-CoV-2 spike-specific effector T-cell responses as early as day 7, peaking at day 14 and maintained up to day 56 as expected with adenoviral vectors. However, a boost in cellular responses was not observed following the second ChAdOx1 nCoV-19 dose. This is consistent with previous findings on viral vectored vaccines given as part of a homologous prime-boost regimen. Severe and fatal cases of COVID-19 disproportionally affect older individuals. Therefore, it is important that vaccines developed to reduce or prevent COVID-19 are suitable for administration in older age groups. Immunogenicity of a ChAdOx1-vectored vaccine against influenza has been shown in older adults (50–78 years of age).As previously reported, anti-vector immunity was low before vaccination in UK adults aged 18–55 years, with no relationship between the presence of antibodies to ChAdOx1 and immune response to the vaccine antigen. Future studies will address the potential effect of anti-vector antibodies on homologous boosting, although in the subgroup reported on here, who received two vaccinations 28 days apart, there was clear evidence of boosting of antibody response to SARS-CoV-2 spike protein.
Limitations of this study include the short follow-up reported to date, the small number of participants in the prime-boost group, and single-blinded design, although staff undertaking clinical evaluation and laboratory staff all remained blinded. Additionally, the study findings are not easily generalisable, as this is a first-in-human study of fairly young and healthy volunteers, the majority of whom were white. Further studies are required to assess the vaccine in various population groups including older age groups, those with comorbidities, and in ethnically and geographically diverse populations. The participants recruited in this study will be followed up for at least 1 year and further safety, tolerability, and immunogenicity (in addition to efficacy) results will be reported when data are available.
In conclusion, ChAdOx1 nCoV-19 was safe, tolerated, and immunogenic, while reactogenicity was reduced with paracetamol. A single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunisation augmenting neutralising antibody titres. The preliminary results of this first-in-human clinical trial supported clinical development progression into ongoing phase 2 and 3 trials. Older age groups with comorbidities, health-care workers, and those with higher risk for SARS-CoV-2 exposure are being recruited and assessed for efficacy, safety, and immunogenicity of ChAdOx1 nCoV-19 given as a single-dose or two-dose administration regimen in further trials conducted in the UK and overseas. We will also evaluate the vaccine in children, once sufficient safety data have been accumulated in adult studies. Phase 3 trials are now underway in Brazil, South Africa, and the UK and will evaluate vaccine efficacy in diverse populations.
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