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Post by Admin on Aug 12, 2020 20:21:36 GMT
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Pedro M Folegatti, MSc * Katie J Ewer, PhD * Parvinder K Aley, PhD Brian Angus, MD
Open Access Published:July 20, 2020 DOI:https://doi.org/10.1016/S0140-6736(20)31604-4
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, and ClinicalTrials.gov, NCT04324606.
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.
Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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Post by Admin on Aug 13, 2020 5:51:10 GMT
Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a zoonotic virus late in 2019 and is the causative agent of COVID-19. Exposure to SARS-CoV-2 can result in a range of clinical outcomes, varying from asymptomatic infection to severe acute respiratory distress and death. SARS-CoV-2 has spread globally and was declared a pandemic on March 11, 2020, by WHO. As of July 19, 2020, more than 14 million people globally have been infected with more than 597 000 deaths.1 The pandemic has placed substantial pressures on health systems delivering care for patients with COVID-19 and caused disruption of non-COVID-19 health-care provision, in addition to negative effects on the global economy. Further health consequences are anticipated. No vaccines have been approved for prevention of COVID-19. There are currently more than 137 candidates undergoing preclinical development and 23 in early clinical development, according to WHO.2 An ideal vaccine against SARS-CoV-2 would be effective after one or two vaccinations; would protect target populations such as older adults and those with comorbidities, including immunocompromised individuals; would confer protection for a minimum of 6 months; and would reduce onward transmission of the virus to contacts. Replication-deficient viral vectored vaccines have been used in immunocompromised individuals with no safety concerns3, 4, 5 and ChAdOx1 vaccines are immunogenic in older adults6 and can be manufactured at large scale, making this platform technology a promising candidate to develop a vaccine for the prevention of COVID-19. Adenoviral vectors have previously been combined with DNA and poxviral vectors to attempt to improve immunogenicity, with adenovirus or modified vaccinia virus Ankara prime-boost regimens showing enhancement of both cellular and humoral immunity. Use of homologous adenoviral regimens has largely been avoided because of presumed induction of antivector immunity, inhibiting the potency of a second dose. Coronaviruses are enveloped, positive sense single-stranded RNA viruses with a glycoprotein spike on the surface, which mediates receptor binding and cell entry during infection. The roles of the spike protein in receptor binding and membrane fusion make it an attractive vaccine antigen. We have previously shown that a single dose of ChAdOx1 MERS, a chimpanzee adenovirus-vectored vaccine that encodes the spike protein of Middle East respiratory syndrome coronavirus (MERS-CoV), protected non-human primates against MERS-CoV-induced disease,7 and data from a phase 1 clinical trial showed that ChAdOx1 MERS was safe and well tolerated at all three doses tested (5 × 109 viral particles, 2·5 × 1010 viral particles, and 5 × 1010 viral particles).8 In addition, the highest dose elicited both humoral and cellular responses against MERS-CoV in all vaccinees within 1 month of vaccination. The ChAdOx1 nCoV-19 vaccine (AZD1222) consists of the replication-deficient simian adenovirus vector ChAdOx1, containing the full-length structural surface glycoprotein (spike protein) of SARS-CoV-2, with a tissue plasminogen activator leader sequence. ChAdOx1 nCoV-19 expresses a codon-optimised coding sequence for the spike protein (GenBank accession number MN908947). In rhesus macaques, a single vaccination with ChAdOx1 nCoV-19 induced humoral and cellular immune responses. Protection against lower respiratory tract infection was observed in vaccinated non-human primates after high-dose SARS-CoV-2 challenge.9 We did a phase 1/2 single-blind, randomised controlled trial of ChAdOx1 nCoV-19 compared with a licensed meningococcal group A, C, W-135, and Y conjugate vaccine (MenACWY; Nimenrix, Pfizer, UK), as control vaccine, in healthy adults in the UK. In this preliminary report, we describe the immunogenicity, reactogenicity, and safety of vaccination with 5 × 1010 viral particles of ChAdOx1 nCoV-19 in single-dose and two-dose regimens. Results Between April 23 and May 21, 2020, 1077 participants were enrolled into the study and assigned to vaccination with either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534; appendix p 3); ten of these participants were enrolled in group 3, the prime-boost group, and thus were not randomly assigned. 88 participants were included in group 1, 412 in group 2, and 567 in group 4 (appendix p 3). All randomised participants were vaccinated; one participant in the MenACWY group received the ChAdOx1 nCoV-19 vaccine (appendix p 3). The median age of participants was 35 years (IQR 28–44 years), 536 (49·8%) participants were female and 541 (50·2%) were male, and the majority of participants (979 [90·9%]) were white (appendix p 4). Baseline characteristics seemed similar between randomised groups (appendix p 4). 56 participants in the ChAdOx1 nCoV-19 group and 57 in the MenACWY group received prophylactic paracetamol. In those who did not receive prophylactic paracetamol, 328 (67%) of 487 participants in the ChAdOx1 nCoV-19 group and 180 (38%) of 477 participants in the MenACWY group reported pain after vaccination, which was mostly mild to moderate in intensity (appendix pp 5–7). With prophylactic paracetamol, pain was reported by fewer participants: 28 (50%) in the ChAdOx1 nCoV-19 group and 18 (32%) in the MenACWY group. Tenderness of mostly mild intensity was reported in the ChAdOx1 nCoV-19 group by 403 (83%) participants without paracetamol and 43 (77%) with paracetamol, and in the MenACWY group by 276 (58%) participants without paracetamol and 26 (46%) with paracetamol (figure 1; appendix pp 5–7). Figure 1 Solicited local (A) and systemic (B) adverse reactions in first 7 days after vaccination as recorded in participant symptom electronic diaries Fatigue and headache were the most commonly reported systemic reactions. Fatigue was reported in the ChAdOx1 nCoV-19 group by 340 (70%) participants without paracetamol and 40 (71%) with paracetamol and in the MenACWY group by 227 (48%) participants without paracetamol and 26 (46%) with paracetamol, whereas headaches were reported in the ChAdOx1 nCoV-19 group by 331 (68%) participants without paracetamol and 34 (61%) with paracetamol and in the MenACWY group by 195 (41%) participants without paracetamol and 21 (37%) participants with paracetamol. Other systemic adverse reactions were common in the ChAdOx1 nCoV-19 group: muscle ache (294 [60%] participants without paracetamol and 27 [48%] with paracetamol), malaise (296 [61%] and 27 [48%]), chills (272 [56%] and 15 [27%]); and feeling feverish (250 [51%] and 20 [36%]). In the of ChAdOx1 nCoV-19 group, 87 (18%) participants without paracetamol and nine (16%) participants with paracetamol reported a temperature of at least 38°C, and eight (2%) patients without paracetamol had a temperature of at least 39°C. In comparison, two (<1%) of those receiving MenACWY reported a fever of at least 38°C, none of whom were receiving prophylactic paracetamol (figure 1; appendix pp 5–7). The severity and intensity of local and systemic reactions was highest on day 1 after vaccination (figure 1). Adjusted analysis of the effect of prophylactic paracetamol on adverse reactions of any severity in the first 2 days after vaccination with ChAdOx1 nCoV-19 showed significant reductions in pain, feeling feverish, chills, muscle ache, headache, and malaise (appendix pp 10–11). All ten participants in the prime-boost group received their booster vaccine at day 28; solicited local and systemic reactions were measured in these participants for 7 days after both the prime and booster doses. The reactogenicity profile after the second dose appeared less severe in this subset, although the small number of participants in this group led to wide CIs (figure 2; appendix pp 8–9).
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Post by Admin on Aug 13, 2020 19:31:04 GMT
Figure 3 SARS-CoV-2 IgG response by standardised ELISA to spike protein in trial participants (A) and in 180 convalescent plasma samples from 172 patients with PCR-confirmed COVID-19 and eight asymptomatic health-care workers (B) Similar increases in serum antibody levels to both the spike protein and the receptor binding domain by day 28 and after a booster dose were observed when measured by MIA (appendix p 16). Immunogenicity among those who were advised to take paracetamol prophylactically was similar to that seen among those who were not advised to use it prophylactically (data not shown). In the PHE PRNT50 assay, which determined the extent to which serum can be diluted and still reduce SARS-CoV-2 plaque formation by 50%, 35 (100%) of 35 participants achieved neutralising titres with a median titre of 218 (IQR 122–395) at day 28 and similar results were obtained with the PHE MNA80 assay, with titres inducing 80% virus neutralisation achieved in 32 (91%) of 35 participants after one dose (median titre 51, 32–103), and in nine (100%) of nine participants after the booster dose (median titre 136, 115–241; figure 4; appendix pp 17–19). In the Marburg VN assay, 23 (62%) of 37 recipients had neutralising antibodies that induced complete inhibition of the cytopathic effect caused by SARS-CoV-2 by day 56 after one dose, as did ten (100%) of ten participants after a booster dose, with a median titre of 29 (24–32; figure 4). Figure 4 Live SARS-CoV-2 neutralisation assays (Marburg VN and PHE PRNT50) and microneutralisation assays (PHE MNA) Titres from the PseudoNA assay and the Marburg VN assay correlated positively with other live virus neutralisation assay titres and with ELISA (PseudoNA R2=0·53 and Marburg VN R2=0·67; both p<0·001; Figure 4, Figure 5; appendix pp 20–21). We included responses following natural exposure as a point of reference for vaccine response data, and found that vaccine-induced responses were in a similar range (figure 5). Interferon-γ ELISpot responses against SARS-CoV-2 spike peptides peaked at 856 spot-forming cells per million peripheral blood mononuclear cells (IQR 493–1802; n=43) at day 14, declining to 424 (221–799; n=43) by day 56 after vaccination (figure 6).
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Post by Admin on Aug 14, 2020 22:14:03 GMT
Figure 5 PseudoNA results in trial participants and in convalescent plasma samples from 146 patients with PCR-confirmed COVID-19 and 24 asymptomatic health-care workers Figure 6 Interferon-γ ELISpot response to peptides spanning the SARS-CoV-2 spike vaccine insert A small number (four [4%] of 98) participants had neutralising antibody titres greater than 8 against SARS-CoV-2 spike protein before vaccination (Marburg VN) and 11 (4%) of 270 participants had high ELISA titres at baseline, representing possible prior asymptomatic infection. Before vaccination, only one (1%) of 98 participants who were tested had high titre (>200) neutralising antibodies against ChAdOx1. Antibodies were detectable at a lower level in a further 18 (1%) participants, and in 79 (81%) participants there were no detectable anti-ChAdOx1 antibodies. We found no relationship between presence of low-level antibodies to ChAdOx1 on the day of vaccination and the ELISA titre to SARS-CoV-2 spike protein in those randomly assigned to receive ChAdOx1 nCoV-19 (appendix p 22). Discussion 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 antigens8, 12, 13, 14 at this dose level, as well as to some licensed vaccines.15 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.8 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.16 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.17, 18 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.19 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.20, 21, 22 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.12 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).6 As previously reported,10 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.23, 24, 25 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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Post by Admin on Sept 9, 2020 5:36:46 GMT
A large, Phase 3 study testing a Covid-19 vaccine being developed by AstraZeneca and the University of Oxford at dozens of sites across the U.S. has been put on hold due to a suspected serious adverse reaction in a participant in the United Kingdom. A spokesperson for AstraZeneca, a frontrunner in the race for a Covid-19 vaccine, said in a statement that the company’s “standard review process triggered a pause to vaccination to allow review of safety data.” In a follow-up statement, AstraZeneca said it initiated the study hold. The nature of the adverse reaction and when it happened were not immediately known, though the participant is expected to recover, according to an individual familiar with the matter. The spokesperson described the pause as “a routine action which has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring we maintain the integrity of the trials.” The spokesperson also said that the company is “working to expedite the review of the single event to minimize any potential impact on the trial timeline.” An individual familiar with the development said researchers had been told the hold was placed on the trial out of “an abundance of caution.” A second individual familiar with the matter, who also spoke on condition of anonymity, said the finding is having an impact on other AstraZeneca vaccine trials underway — as well as on the clinical trials being conducted by other vaccine manufacturers. Clinical holds are not uncommon, and it’s unclear how long AstraZeneca’s might last. But the progress of the company’s trial — and those of all Covid-19 vaccines in development — are being closely watched given the pressing need for new ways to curb the global pandemic. There are currently nine vaccine candidates in Phase 3 trials. AstraZeneca’s is the first Phase 3 Covid-19 vaccine trial known to have been put on hold. Researchers running other trials are now looking for similar cases of adverse reactions by combing through databases reviewed by a so-called Data and Safety Monitoring Board, the second person said.
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