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Post by Admin on Apr 5, 2021 22:05:56 GMT
Data from a UK phase 2/3 clinical trial suggest the AstraZeneca-Oxford COVID-vaccine is 70.4% effective against symptomatic COVID-19 caused by the B117 variant, which was identified in the United Kingdom in late 2020.
The data, published in The Lancet yesterday, also showed it was 28.9% effective at preventing asymptomatic infections or cases with unknown symptoms.
Overall efficacy was 61.7% against the B117 variant and 77.3% against other variants, according to the study. The vaccine was 81.5% effective in preventing symptomatic COVID-19 caused by non-B117 strains.
In a Lancet commentary, Rogier W. Sanders, PhD, and Menno D. de Jong, MD, PhD, of Amsterdam University Medical Centers, write, "Given the wide CIs [confidence intervals] in these exploratory analyses, no firm conclusions can be drawn on the precise clinical efficacy against the B.1.1.7 variant and, importantly, how this efficacy compares with efficacy against the original circulating variants."
Even so, they say the findings "suggest a meaningful degree of efficacy against the B.1.1.7 variant, which is encouraging."
The AstraZeneca vaccine is being rolled out in the United Kingdom, countries participating in the World Health Organization's (WHO's) COVAX initiative, and elsewhere. Both the AstraZeneca and Johnson & Johnson vaccine use viral vector technology, as opposed to the mRNA method that the Pfizer/BioNTech and Moderna COVID-19 vaccines use.
Good protection despite lower immune response From May 31 to Nov 13, 2020, the researchers recruited 8,534 adults from England, Wales, and Scotland. Participants randomly received the intervention (the AstraZeneca vaccine) or a meningococcal control vaccine in a 1:1 ratio. All participants received their second dose from Aug 3 to Dec 30, 2020, and each week the researchers asked the cohort to report any COVID-19 symptoms and requested an upper respiratory swab sample.
A little over 6% were infected with COVID-19 more than 2 weeks after their booster shot (520 cases, 33.3% of whom received the intervention). Genetic sequences were available for 311 cases, and in an examination of 219, the researchers found that B117 caused 35.4% of the 147 symptomatic cases and 35.8% of the asymptomatic cases.
Their results indicate that the AstraZeneca vaccine efficacy was 70.4% (95% CI, 43.6 to 84.5) against symptomatic COVID-19 caused by B117 and 81.5% (95% CI, 67.9 to 89.4) against non-B117 symptomatic COVID-19. Efficacy for asymptomatic/unknown symptom cases was lower both for B117 (28.9%; 95% CI, -77.1 to 71.4) and other strains (69.7%; 95% CI, 33.0 to 86.3).
Forty-nine participants in the intervention group also were part of a blood test, and the researchers found that the vaccine's neutralizing titers were 8.9 times lower against B117 than the Victoria lineage, which is much more similar to the original strain first identified in Wuhan, China.
"Despite the large reduction in measured live neutralising activity against B.1.1.7 virus, the vaccine provided strong protection against B.1.1.7 variant disease, with the lower bound of the 95% CI above the 30% threshold recommended by WHO," the researchers write.
No participants required hospital admission or died from COVID-19 infection. Most (77.8%) were 18 to 55 years old, 59.3% were female, and 92.1% were White.
COVID in vaccinated; dose differences Compared with the control group, those who received the AstraZeneca-Oxford vaccine tested positive on a nucleic acid amplification test for less time (median, 1 week vs 2 weeks) and had a lower viral load, indicated by a cycle threshold (Ct) value (median 28.8 vs 20.2, where a higher Ct indicates less viral RNA).
The researchers did not find any significant differences between duration or viral loads caused by B117 and non-B117 COVID strains. They did, however, note that symptomatic patients had a higher viral load than those with asymptomatic or unknown infections (median Ct, 18.2 vs 29.7, respectively) and tested positive for longer.
In further exploration of the vaccine's efficacy, a different subset of the intervention cohort received a regimen of low-dose/standard-dose (LD/SD) vaccination as opposed to two standard doses (SD/SD). The SD/SD group made up 36 of 52 symptomatic B117 cases (69.2%) and 61 of 95 symptomatic non-B117 cases (64.2%), so vaccine efficacy was higher in the LD/SD group by 9.2 to 11.2 percentage points.
"Here, we show that the ChAdOx1 nCoV-19 [AstraZeneca] vaccine provides protection against symptomatic disease caused by the novel B.1.1.7 lineage," the researchers conclude. "Vaccination with ChAdOx1 nCoV-19 also results in a reduction in the duration of shedding and viral load, which might reduce transmission of disease, supporting the ongoing use of this vaccine to protect populations at risk of disease."
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Post by Admin on Apr 6, 2021 0:41:54 GMT
Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant
Shabir A. Madhi, Ph.D., Vicky Baillie, Ph.D., Clare L. Cutland, Ph.D., Merryn Voysey, D.Phil., et al., for the NGS-SA Group Wits–VIDA COVID Group*
March 16, 2021 DOI: 10.1056/NEJMoa2102214
Abstract BACKGROUND Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa.
METHODS We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose.
RESULTS Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], −49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, −76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups.
CONCLUSIONS A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674. opens in new tab; Pan African Clinical Trials Registry number, PACTR202006922165132. opens in new tab).
Introduction Development of vaccines to prevent coronavirus disease 2019 (Covid-19) has occurred with unprecedented speed.1-4 ChAdOx1 nCoV-19, a replication-deficient chimpanzee adenoviral vector containing the sequence for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structural surface glycoprotein antigen, is one of six Covid-19 vaccines based on different platforms that have been authorized for emergency use,5-11 with efficacy results for two additional vaccines having recently been reported.12,13
Meanwhile, the SARS-CoV-2 spike gene has accumulated mutations within the receptor-binding domain (RBD) and the N-terminal domain (NTD).14,15 These domains are major targets of the antibody response elicited by the vaccines. The RBD mutations include the N501Y mutation, which is associated with increased affinity of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor.16 In contrast, the E484K and K417N RBD mutations and mutations in the NTD have been associated with neutralizing antibody escape.17 The B.1.1.7 (N501Y.V1) lineage, first identified in the United Kingdom, includes the N501Y mutation, which has been associated with 53% increased transmissibility.18 Neutralizing antibody activity elicited by infection or by mRNA vaccines against the B.1.1.7 variant are largely unaffected.19 The B.1.1.7 variant, however, has now evolved to include the E484K mutation in the United Kingdom.20
The B.1.351 (N501Y.V2) lineage first identified in South Africa contains the three RBD mutations and five additional NTD mutations.14,15 The sensitivity of B.1.351 to neutralizing antibodies from convalescent donors infected with the prototype lineage virus, assessed with a spike-pseudovirus neutralization assay, indicated that 48% of serum samples were unable to neutralize B.1.351, with the rest showing a reduction in neutralization titers by a factor of 3 to 86.21 This finding was corroborated by a live-virus neutralization assay, with reduction in antibody activity ranging from a factor of 6 to complete knockout for the B.1.351 variant.14 Another independent lineage of SARS-CoV-2 (P.1) also containing the E484K, K417N, and some B.1.351 NTD mutations has been identified in Brazil.22,23
A pooled analysis of the efficacy of the ChAdOx1 nCoV-19 vaccine in the United Kingdom, Brazil, and South Africa, performed before the emergence of the B.1.351 and P.1 variants, reported an overall vaccine efficacy of 66.7% (95.8% confidence interval [CI], 57.4 to 74.0).24 Recent analysis of the efficacy of the ChAdOx1 nCoV-19 vaccine against the B.1.1.7 variant in the United Kingdom was 74.6% (95% CI, 41.6 to 88.9).25
Here, we report findings from a multicenter phase 1b–2 trial in South Africa evaluating the safety, immunogenicity, and efficacy of the ChAdOx1 nCoV-19 vaccine in preventing symptomatic Covid-19. This interim analysis is limited to addressing the primary objective evaluating safety and the primary and key secondary objectives evaluating vaccine efficacy, including efficacy specifically against the B.1.351 variant. Furthermore, we report on immunogenicity of ChAdOx1 nCoV-19 and on post hoc pseudovirus and live-virus neutralization assay investigations of the sensitivity of the original D614G virus and the B.1.351 variant to vaccine-elicited antibodies.
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Post by Admin on Apr 6, 2021 2:44:24 GMT
Methods TRIAL OBJECTIVES, PARTICIPANTS, AND OVERSIGHT In this multisite, double-blind, randomized, placebo-controlled trial conducted in South Africa, we assessed the safety and efficacy of two standard doses of the ChAdOx1 nCoV-19 vaccine, administered 21 to 35 days apart, as compared with saline (0.9% sodium chloride) placebo. Adults 18 to less than 65 years of age, with no or well-controlled chronic medical conditions, were eligible for participation. Included among the participants were 70 HIV-negative persons enrolled as group 1, in whom intensive safety and immunogenicity studies were planned. Key exclusion criteria were human immunodeficiency virus (HIV) positivity at screening (for the efficacy cohort), previous or current laboratory-confirmed Covid-19, a history of anaphylaxis in relation to vaccination, and morbid obesity (body-mass index [BMI, the weight in kilograms divided by the square of the height in meters], ≥40). Detailed inclusion and exclusion criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. The ChAdOx1 nCoV-19 vaccine was developed at the University of Oxford, which was responsible for the conduct and oversight of the trial (see the Supplementary Appendix).
The authors had full access to the trial data, confirm the accuracy and completeness of the data reported, and vouch for the fidelity of the trial to the protocol (available at NEJM.org). An independent data and safety monitoring committee reviewed efficacy and unblinded safety data. A local trial-safety physician reviewed all serious adverse events as they occurred. The trial was monitored by an external clinical research organization, which ensured adherence to the protocol.
The trial was reviewed and approved by the South African Health Products Regulatory Authority and by the ethics committees of the University of the Witwatersrand, Cape Town, Stellenbosch, and OxTREC before trial initiation. All participants were fully informed about the trial procedures and the possible risks, and all signed written informed consent documents before enrollment in the trial.
TRIAL PROCEDURES Trial participants were randomly assigned to receive either a 0.33-to-0.5-ml dose (depending on the lot) of the ChAdOx1 nCoV-19 vaccine or placebo by intramuscular injection on the day of randomization and a second injection 21 to 35 days later. Injections were administered into the deltoid muscle of the nondominant arm, and participants were observed for 30 minutes after the injection for acute reactions. Injections were prepared and administered by site staff who were aware of participants’ trial-group assignments but were not involved in any other trial procedures. Trial participants and all other trial staff remain unaware of trial-group assignments. Details of the trial procedures are provided in the protocol (pages 68–73). Follow-up is ongoing.
SAFETY The safety analysis evaluated the occurrence of solicited local and systemic reactogenicity within the first 7 days after an injection, unsolicited adverse events within 28 days after an injection, changes from baseline in safety laboratory measures, and serious adverse events. Further details of methods used to evaluate safety and reactogenicity are provided in the Supplementary Appendix. Adverse event data through January 15, 2021, are included in this report.
SARS-COV-2 TESTING, WHOLE-GENOME SEQUENCING, AND GENOME ASSEMBLY Use of a nucleic acid amplification test for SARS-CoV-2 infection included sampling at routine scheduled visits (detailed in the protocol) and at nonroutine visits when participants had any symptom suggestive of Covid-19 illness. Participants were advised at the time of randomization as to which clinical symptoms should trigger a visit for investigation of possible SARS-CoV-2 infection (Table S1 in the Supplementary Appendix). In addition, short messages were sent to participants every 2 weeks as a reminder to present for investigation if they had symptoms. Details of nucleic acid amplification testing, whole-genome sequencing, and phylogenetic analysis are described in Supplementary Appendix.
NEUTRALIZATION ASSAYS SARS-CoV-2 serostatus at randomization was evaluated with the use of an IgG assay of the nucleoprotein (N), as described elsewhere.8 For antibody-neutralization studies, pseudovirus neutralization assays (see the Methods section in the Supplementary Appendix) were performed at Monogram Biosciences, to prototype virus on serum samples obtained 2 weeks after the second dose of vaccine in 107 randomly selected ChAdOx1 nCoV-19 vaccine recipients who were seronegative for IgG N protein at enrollment.
To assess neutralization activity of vaccine-elicited antibodies against B.1.351, serum samples from group 1 participants who had negative SARS-CoV-2 serostatus at enrollment and varying pseudovirus neutralization assay titers to the original D614G spike virus at 14 days after the second injection were tested with pseudovirus and live-virus neutralization assays for activity against the B.1.351 variant.14,21 Testing of neutralizing antibody activity against the original virus and the B.1.351 variant was undertaken before unblinding of trial-group assignments. The pseudovirus assays for neutralization activity against the original D614G spike, an RBD triple mutant (containing only K417N, E484K, and N501Y), and the B.1.351 spike were performed at the National Institute for Communicable Diseases (South Africa).14 Live-virus neutralization assay testing was performed by a microneutralization focus-forming assay in Vero E6 cells at the African Health Research Institute, South Africa.14,21 Details of the pseudovirus and live-virus neutralization assays have been published and are described briefly in the Supplementary Appendix.14,21
EFFICACY OBJECTIVES The primary end point was efficacy against nucleic acid amplification test–confirmed symptomatic Covid-19 with onset more than 14 days after the second injection in participants who were seronegative at randomization. Confirmed symptomatic Covid-19 and the grading of mild, moderate, and severe disease were prespecified and are defined in Tables S1 and S2. Covid-19 cases were evaluated by at least two physicians who were independent of the trial and were unaware of trial-group assignments. Discordant assessments were discussed between the two reviewers. Vaccine efficacy against the B.1.351 variant was a prespecified secondary objective.
Other secondary efficacy objectives included efficacy against Covid-19 in the overall population (including participants who were seropositive at randomization), efficacy specific to the baseline seropositive group, and efficacy against Covid-19 with onset more than 14 or more than 21 days after the first dose. Further details of secondary efficacy analyses are included in the Supplementary Appendix. Furthermore, a post hoc analysis was performed for the overall and seronegative populations, to evaluate vaccine efficacy against illness occurring more than 14 days after the first injection, with end-point cases restricted until October 31, 2020, as a proxy for non–B.1.351 variant Covid-19. The B.1.351 variant only began to be identified in the areas where the trial sites (Johannesburg and Tshwane in Gauteng, and Cape Metro in Western Cape Province) were based from mid-November 2020 onward (Fig. S1).15
STATISTICAL ANALYSIS Participants who received at least one dose of the ChAdOx1 nCoV-19 vaccine or placebo and who returned diary cards completed until day 7 after the first injection were included in the safety reactogenicity analysis. The occurrence of each solicited local and systemic reactogenicity sign and symptom for 7 days after vaccination, adverse events, and serious adverse events through January 15, 2021, are presented according to trial group.
The primary efficacy analysis was end-point–driven for the composite of mild, moderate, or severe Covid-19 and required 42 cases to detect a vaccine efficacy of at least 60% (with a lower bound of 0% for the 95% confidence interval), with 80% power. Vaccine efficacy was calculated as 1 minus the relative risk, and 95% confidence intervals calculated with the Clopper–Pearson exact method are reported. Only participants in the per-protocol population (all participants who received two doses of vaccine or placebo and were grouped according to the injection they received, regardless of their planned group assignment) who were seronegative for SARS-CoV-2 at enrollment were included in the primary efficacy analysis. A sensitivity analysis was conducted that included seronegative participants in the modified intention-to-treat population (all participants who received two doses and were grouped by their planned assignment, irrespective of the injection they received). Confidence intervals reported in this article have not been adjusted for multiple comparisons.
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Post by Admin on Apr 6, 2021 6:22:08 GMT
Figure 1. Results PARTICIPANTS Enrollment of Participants, Randomization, Vaccine or Placebo Administration, and Follow-up. We screened 3022 persons across seven sites and enrolled 2026 HIV-negative persons in the trial between June 24 and November 9, 2020. All participants except 5 who did not receive vaccine or placebo were included in the safety analysis. The initiation of enrollment coincided with the peak of the first Covid-19 wave in South Africa (Fig. S2). Overall, 1011 participants received the vaccine and 1010 received the placebo (Figure 1). A total of 1467 seronegative participants (750 assigned to the vaccine and 717 to placebo) were eligible for the primary efficacy analysis; reasons for exclusion are listed in Figure 1. The median age of the participants was 30 years, 56.5% identified as male, and the racial distribution included 70.5% Black Africans, 12.8% Whites, and 14.9% identifying as mixed race. Nineteen percent of participants were obese (BMI, 30 to 39.9), 42.0% were smokers, 2.8% had underlying hypertension, and 3.1% had chronic respiratory conditions. The median time between doses was 28 days, and the median duration of follow-up from enrollment and from 14 days after the second dose of vaccine or placebo was 156 and 121 days, respectively (as of January 15, 2021). Demographic characteristics of the baseline seronegative population were similar to those of the overall population (Table 1). SAFETY Local and systemic reactogenicity data are presented in Figures S3 and S4. The incidence of adverse events and serious adverse events was similar among vaccine and placebo recipients (Tables S3 and S4). The only serious adverse event attributed to the ChAdOx1 nCoV-19 vaccine was a body temperature above 40°C after the first dose; the fever subsided within 24 hours, and no reactogenicity was observed after the second dose. All other events were considered unrelated or unlikely to be related to the injection received.
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Post by Admin on Apr 6, 2021 20:15:11 GMT
IMMUNOGENICITY Figure 2. Pseudovirus and Live-Virus Neutralization Assay Findings. Humoral response to the ChAdOx1 nCoV-19 vaccine induced strong neutralizing antibodies at 28 days after the first dose (geometric mean titer, 132; interquartile range, 20 to 404), which rose further after a second dose (geometric mean titer, 277; interquartile range, 124 to 526) (Figure 2A and Table S5). There were 25 participants in group 1 (the group of 70 participants who also had laboratory measures evaluated as part of their safety analysis) who were SARS-CoV-2 seronegative at enrollment and had neutralizing antibody activity against the original D614G virus on the pseudovirus neutralization assay at 14 days after the second dose. The serum samples from these participants, obtained 14 days after the second dose, were further tested with pseudovirus and live-virus assays for neutralizing activity against the B.1.351 variant. After unblinding of the data, 6 of the 25 serum samples were identified as having been obtained from placebo recipients likely to have been infected with the original SARS-CoV-2 (which predated the emergence of the B.1.351 variant in South Africa) during the follow-up period. Furthermore, nucleic acid amplification testing showed that 6 of the vaccine recipients were also infected with SARS-CoV-2 by 14 days after the second dose. Six of 13 vaccine recipients (46%) without evidence of previous SARS-CoV-2 infection showed no neutralization activity against an RBD triple-mutant pseudovirus (containing K417N, E484K, and N501Y variants), and 11 of the 13 (85%) had no neutralization activity against B.1.351 pseudovirus (Figure 2B). Geometric mean titers dropped from 297 against the original virus to 85 against the RBD-only mutant and 74 against the B.1.351 variant. Vaccine recipients with nucleic acid amplification test–confirmed illness (before the emergence of B.1.351) showed results similar to those among participants with no confirmed illness (Fig. S6). Samples from the SARS-CoV-2–infected placebo recipients showed similarly low neutralizing activity, with residual titers of less than 100 (or undetectable) against the RBD triple-mutant pseudovirus and the B.1.351 variant (Figure 2B). Live-virus assay showed lower neutralization overall, relative to pseudovirus assay (Figure 2C). Of the 13 vaccine recipients without evidence of previous SARS-CoV-2 infection before or during follow-up, one had undetectable neutralization activity against B.1.1 and B.1.351. Seven of the 12 participants (58%) with neutralization activity against B.1.1 had undetectable neutralization activity against the B.1.351 variant, and the remaining 5 showed neutralization that was lower by a factor of 4.1 to 31.5 (Figure 2C). As with the pseudovirus neutralization assay, six vaccine recipients with nucleic acid amplification test–confirmed illness showed results similar to those among participants with no confirmed illness (Fig. S6B, light gray points). Among the six placebo recipients recently infected with SARS-CoV-2, all had detectable neutralization of the B.1.1 variant, whereas neutralization activity against the B.1.351 variant was undetectable in two cases, lower neutralization by a factor of 6.0 to 9.5 was noted in three cases, and no change was seen in one case (Figure 2C). Given the potential importance of T cells in protection from severe disease,26 we include data on 17 recipients of the ChAdOx1 nCoV-19 vaccine from the United Kingdom, who were evaluated with T-cell–receptor variable beta-chain sequencing for expansion of spike-specific T cells (see the Supplementary Appendix). The ChAdOx1 nCoV-19 vaccine caused expansion of CD4+ and CD8+ T lymphocytes to specific epitopes of the spike protein. Of 87 spike-specific antigens identified by the sequencing, 75 remained unaffected by the B.1.351 mutations. Of note, the D215G mutation found in the B.1.351 variant is within a region that had prevalent T-cell antigen responses (Fig. S7).
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