Post by Admin on Jul 4, 2021 20:26:56 GMT
Discussion
This international, phase 3 ENSEMBLE trial showed the efficacy of a single dose of the Ad26.COV2.S vaccine in preventing Covid-19. Efficacy against moderate to severe–critical Covid-19 was 67% against disease with onset at least 14 days after administration and 66% against disease with onset 28 days after administration. Because the number of primary end-point cases was similar to the number of cases according to the FDA harmonized definition, this estimate essentially captures most of the cases of symptomatic Covid-19. Higher efficacy against severe–critical Covid-19 was observed, with vaccine efficacy of 77% against disease with onset at least 14 days after administration and 85% against disease with onset at least 28 days after administration.
The onset of efficacy was evident as of 14 days after administration for moderate to severe–critical disease and as of 7 days after administration for severe–critical disease. Efficacy continued to increase through approximately 8 weeks after administration, especially for severe–critical Covid-19. No evidence of waning efficacy was noted among the approximately 3000 participants who were followed for 11 weeks or among 1000 participants who were followed for 15 weeks, a finding that is consistent with the persistence of humoral immunity that was observed in a phase 1–2a trial.9
Efficacy against severe–critical Covid-19 was consistently high overall and in individual countries that had sufficient cases for analysis, which is particularly important because severe disease has the greatest effect on individual persons and health care systems.19 Efficacy against Covid-19 involving hospitalization was 93% with regard to onset at least 14 days after administration (2 cases in the vaccine group and 29 in the placebo group) and 100% with regard to onset at least 28 days after administration (no hospitalizations in the vaccine group and 16 in the placebo group). Although hospitalization can be influenced by local practice and resource availability, all the hospitalizations that were reported were justified by clear clinical findings and were consistent across countries. Moreover, identical management practices would have applied to the Ad26.COV2.S group and the placebo group in each country. Five deaths that were related to Covid-19 occurred in the placebo group, but there were no such deaths in the vaccine group. The reduction in the incidence of death and the high efficacy against hospitalization are expected to substantially reduce the effect of this disease on individual persons and dramatically decrease the burden on health care systems.
Vaccine recipients with breakthrough Covid-19 reported fewer and less severe symptoms than did placebo recipients with Covid-19, which suggests that illness is milder after vaccination. The data are consistent with studies reporting higher efficacy of the influenza vaccine against more severe influenza20-22 and the attenuation of influenza among vaccinees.23-25 A preliminary analysis indicated that Ad26.COV2.S provided at least 66% protection against serologically confirmed asymptomatic infection with SARS-CoV-2. The effect on the incidence of symptomatic and asymptomatic SARS-CoV-2 infection by the vaccine suggests that it might be useful in reducing community-wide transmission.
New SARS-CoV-2 virus lineages have emerged, with mutations in the N-terminal and receptor-binding domains of the spike protein that are known targets for neutralizing antibodies; in particular, the E484K mutation is associated with reduced neutralization sensitivity.26-31 Of main concern are variants that were first identified in Brazil, South Africa, and the United Kingdom.2-4 In our trial, 95% of the Covid-19 cases in South Africa in which SARS-CoV-2 was sequenced were caused by the 20H/501Y.V2 variant, whereas a variant from the P.2 lineage carrying the E484K mutation was identified in 69% of the cases in Brazil with a sequenced sample. However, despite the high prevalence of SARS-CoV-2 variants of concern, vaccine efficacy remained high. This finding shows that a Covid-19 vaccine that was based on the original Wuhan-Hu-1 strain can elicit cross-protective efficacy against new variants in South Africa and Brazil. Nonneutralizing antibodies against SARS-CoV-2 variants are probably preserved because they are not limited to the N-terminal or receptor-binding domains, where most mutations occur. Antibodies with Fc-mediated functions are induced by Ad26.COV2.S against SARS-CoV-2 in humans,32 and these Fc functional antibodies show no decrease in potency against new variants (personal communication: G. Alter and D. Barouch). In addition, CD8+ T-cell responses to the SARS-CoV-2 spike protein were seen in a phase 1–2a trial.9 T-cell epitopes were shown to be conserved between SARS-CoV-2 variants according to immunoinformatics analyses.33-35 These factors might contribute to the high efficacy against severe–critical disease, hospitalization, and death in South Africa, where the relatively neutralization-resistant 20H/501Y.V2 variant predominates.26,36
Efficacy against symptomatic infection was similar among younger and older participants and among participants with coexisting conditions and those without coexisting conditions. A subgroup analysis involving participants 60 years of age or older showed that vaccine efficacy against symptomatic disease with onset at least 14 days after administration was similar in subgroups defined according to the presence or absence of coexisting conditions. With regard to onset at least 28 days after administration, vaccine efficacy appeared lower among participants with coexisting conditions than among those without coexisting conditions. This finding can be attributed to imprecision owing to fewer cases and shorter follow-up in this subgroup. Furthermore, Kaplan–Meier curves indicated that the cumulative incidence of cases among vaccine recipients 60 years of age or older with coexisting conditions was similar to that in the overall trial population, which suggests a similar vaccine efficacy. Vaccine efficacy against hospitalization among vaccine recipients 60 years of age or older with coexisting conditions was 82%, a finding consistent with this result.
This trial confirmed the findings from a phase 1–2a trial9 showing that Ad26.COV2.S had an acceptable safety and reactogenicity profile. Reactogenicity to Ad26.COV2.S was transient, was lower in older participants than in younger participants, and resolved quickly. Severe reactogenicity (grade ≥3) was uncommon, and serious adverse events were rare. Data from the current trial are supported by long-term and robust safety data on the Ad26 platform.10-12
A key strength of this trial is that it showed vaccine efficacy in an ethnically and geographically diverse population, including participants in regions with emerging SARS-CoV-2 variants, as well as in participants with coexisting conditions that have been associated with an increased risk of severe Covid-19. A limitation of the trial is the relatively short follow-up, which was necessitated, as in other Covid-19 vaccine trials, by the urgent need for vaccine. The data do not suggest a waning of protection. Long-term unblinded follow-up is planned to compare results in initial Ad26.COV2.S recipients with those in placebo recipients who are expected to receive Ad26.COV2.S after a protocol amendment has been approved.
This trial was conducted during a time of an extraordinarily high incidence of SARS-CoV-2 infection. Lower vaccine efficacy has been associated with a higher incidence of disease.37-39 This situation, combined with the emergence of viral variants, precludes the comparison of vaccine trials. In this trial, we robustly field-tested a simple regimen under high attack-rate conditions on three continents and consistently found early and increasing protection from severe disease.
In this trial, we found that a single dose of Ad26.COV2.S protected against symptomatic Covid-19 and was particularly efficacious against severe–critical disease (including hospitalization and death), including in countries where variants that are considered to be relatively resistant to antibody neutralization predominate. Safety appeared to be similar to that seen in previous phase 3 trials of Covid-19 vaccines. The single-dose schedule and favorable storage conditions of this vaccine provide major advantages in its deployment and effect worldwide.
This international, phase 3 ENSEMBLE trial showed the efficacy of a single dose of the Ad26.COV2.S vaccine in preventing Covid-19. Efficacy against moderate to severe–critical Covid-19 was 67% against disease with onset at least 14 days after administration and 66% against disease with onset 28 days after administration. Because the number of primary end-point cases was similar to the number of cases according to the FDA harmonized definition, this estimate essentially captures most of the cases of symptomatic Covid-19. Higher efficacy against severe–critical Covid-19 was observed, with vaccine efficacy of 77% against disease with onset at least 14 days after administration and 85% against disease with onset at least 28 days after administration.
The onset of efficacy was evident as of 14 days after administration for moderate to severe–critical disease and as of 7 days after administration for severe–critical disease. Efficacy continued to increase through approximately 8 weeks after administration, especially for severe–critical Covid-19. No evidence of waning efficacy was noted among the approximately 3000 participants who were followed for 11 weeks or among 1000 participants who were followed for 15 weeks, a finding that is consistent with the persistence of humoral immunity that was observed in a phase 1–2a trial.9
Efficacy against severe–critical Covid-19 was consistently high overall and in individual countries that had sufficient cases for analysis, which is particularly important because severe disease has the greatest effect on individual persons and health care systems.19 Efficacy against Covid-19 involving hospitalization was 93% with regard to onset at least 14 days after administration (2 cases in the vaccine group and 29 in the placebo group) and 100% with regard to onset at least 28 days after administration (no hospitalizations in the vaccine group and 16 in the placebo group). Although hospitalization can be influenced by local practice and resource availability, all the hospitalizations that were reported were justified by clear clinical findings and were consistent across countries. Moreover, identical management practices would have applied to the Ad26.COV2.S group and the placebo group in each country. Five deaths that were related to Covid-19 occurred in the placebo group, but there were no such deaths in the vaccine group. The reduction in the incidence of death and the high efficacy against hospitalization are expected to substantially reduce the effect of this disease on individual persons and dramatically decrease the burden on health care systems.
Vaccine recipients with breakthrough Covid-19 reported fewer and less severe symptoms than did placebo recipients with Covid-19, which suggests that illness is milder after vaccination. The data are consistent with studies reporting higher efficacy of the influenza vaccine against more severe influenza20-22 and the attenuation of influenza among vaccinees.23-25 A preliminary analysis indicated that Ad26.COV2.S provided at least 66% protection against serologically confirmed asymptomatic infection with SARS-CoV-2. The effect on the incidence of symptomatic and asymptomatic SARS-CoV-2 infection by the vaccine suggests that it might be useful in reducing community-wide transmission.
New SARS-CoV-2 virus lineages have emerged, with mutations in the N-terminal and receptor-binding domains of the spike protein that are known targets for neutralizing antibodies; in particular, the E484K mutation is associated with reduced neutralization sensitivity.26-31 Of main concern are variants that were first identified in Brazil, South Africa, and the United Kingdom.2-4 In our trial, 95% of the Covid-19 cases in South Africa in which SARS-CoV-2 was sequenced were caused by the 20H/501Y.V2 variant, whereas a variant from the P.2 lineage carrying the E484K mutation was identified in 69% of the cases in Brazil with a sequenced sample. However, despite the high prevalence of SARS-CoV-2 variants of concern, vaccine efficacy remained high. This finding shows that a Covid-19 vaccine that was based on the original Wuhan-Hu-1 strain can elicit cross-protective efficacy against new variants in South Africa and Brazil. Nonneutralizing antibodies against SARS-CoV-2 variants are probably preserved because they are not limited to the N-terminal or receptor-binding domains, where most mutations occur. Antibodies with Fc-mediated functions are induced by Ad26.COV2.S against SARS-CoV-2 in humans,32 and these Fc functional antibodies show no decrease in potency against new variants (personal communication: G. Alter and D. Barouch). In addition, CD8+ T-cell responses to the SARS-CoV-2 spike protein were seen in a phase 1–2a trial.9 T-cell epitopes were shown to be conserved between SARS-CoV-2 variants according to immunoinformatics analyses.33-35 These factors might contribute to the high efficacy against severe–critical disease, hospitalization, and death in South Africa, where the relatively neutralization-resistant 20H/501Y.V2 variant predominates.26,36
Efficacy against symptomatic infection was similar among younger and older participants and among participants with coexisting conditions and those without coexisting conditions. A subgroup analysis involving participants 60 years of age or older showed that vaccine efficacy against symptomatic disease with onset at least 14 days after administration was similar in subgroups defined according to the presence or absence of coexisting conditions. With regard to onset at least 28 days after administration, vaccine efficacy appeared lower among participants with coexisting conditions than among those without coexisting conditions. This finding can be attributed to imprecision owing to fewer cases and shorter follow-up in this subgroup. Furthermore, Kaplan–Meier curves indicated that the cumulative incidence of cases among vaccine recipients 60 years of age or older with coexisting conditions was similar to that in the overall trial population, which suggests a similar vaccine efficacy. Vaccine efficacy against hospitalization among vaccine recipients 60 years of age or older with coexisting conditions was 82%, a finding consistent with this result.
This trial confirmed the findings from a phase 1–2a trial9 showing that Ad26.COV2.S had an acceptable safety and reactogenicity profile. Reactogenicity to Ad26.COV2.S was transient, was lower in older participants than in younger participants, and resolved quickly. Severe reactogenicity (grade ≥3) was uncommon, and serious adverse events were rare. Data from the current trial are supported by long-term and robust safety data on the Ad26 platform.10-12
A key strength of this trial is that it showed vaccine efficacy in an ethnically and geographically diverse population, including participants in regions with emerging SARS-CoV-2 variants, as well as in participants with coexisting conditions that have been associated with an increased risk of severe Covid-19. A limitation of the trial is the relatively short follow-up, which was necessitated, as in other Covid-19 vaccine trials, by the urgent need for vaccine. The data do not suggest a waning of protection. Long-term unblinded follow-up is planned to compare results in initial Ad26.COV2.S recipients with those in placebo recipients who are expected to receive Ad26.COV2.S after a protocol amendment has been approved.
This trial was conducted during a time of an extraordinarily high incidence of SARS-CoV-2 infection. Lower vaccine efficacy has been associated with a higher incidence of disease.37-39 This situation, combined with the emergence of viral variants, precludes the comparison of vaccine trials. In this trial, we robustly field-tested a simple regimen under high attack-rate conditions on three continents and consistently found early and increasing protection from severe disease.
In this trial, we found that a single dose of Ad26.COV2.S protected against symptomatic Covid-19 and was particularly efficacious against severe–critical disease (including hospitalization and death), including in countries where variants that are considered to be relatively resistant to antibody neutralization predominate. Safety appeared to be similar to that seen in previous phase 3 trials of Covid-19 vaccines. The single-dose schedule and favorable storage conditions of this vaccine provide major advantages in its deployment and effect worldwide.