VAXZEVRIA Suspension for injection Ref.[11061] Active ingredients: SARS-CoV-2 Spike glycoprotein (ChAdOx1-S)

Pharmacotherapeutic group: Vaccines, other viral vaccines
ATC code: J07BX03

Mechanism of action

Vaxzevria is a monovalent vaccine composed of a single recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1) vector encoding the S glycoprotein of SARS-CoV-2. The SARS-CoV-2 S immunogen in the vaccine is expressed in the trimeric pre-fusion conformation; the coding sequence has not been modified in order to stabilise the expressed S-protein in the pre-fusion conformation. Following administration, the S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralising antibody and cellular immune responses, which may contribute to protection to COVID-19.

Clinical efficacy

Analysis of data from Study D8110C00001

The clinical efficacy of Vaxzevria has been evaluated based on an analysis of Study D8110C00001: a randomised, double-blinded, placebo-controlled phase III study conducted in the United States, Peru and Chile. The study excluded participants with severe and/or uncontrolled cardiovascular, gastrointestinal, liver, renal, endocrine/metabolic disease, and neurological illnesses; as well as those with severe immunosuppression, pregnant women and participants with a known history of SARS-CoV-2 infection. All participants are planned to be followed for up to 12 months, for assessments of efficacy against COVID-19 disease.

Participants ≥18 years of age received two doses (5 × 10¹⁰ viral particles per dose corresponding to not less than 2.5 × 10⁸ infectious units) of Vaxzevria (N=17,662) or saline placebo (N=8,550), administered via IM injection on Day 1 and Day 29 (-3 to +7 days). The median dose interval was 29 days and the majority of participants (95.7% and 95.3% for Vaxzevria and placebo, respectively) received the second dose ≥26 to ≤36 days after dose 1.

Baseline demographics were well balanced across the Vaxzevria and placebo groups. Of the participants who received Vaxzevria, 79.1% were aged 18 to 64 years (with 20.9% aged 65 or older) and 43.8% of subjects were female. Of those randomised, 79.3% were White, 7.9% were Black, 4.2% were Asian, 4.2% were American Indian or Alaska Native. A total of 10,376 (58.8%) participants had at least one pre-existingcomorbidity, defined as: chronic kidney disease, chronic obstructive pulmonary disease, lower immune health because of a solid organ transplant, history of obesity (BMI >30), serious heart conditions, sickle cell disease, type 1 or 2 diabetes, asthma, dementia,cerebrovascular diseases, cystic fibrosis, high blood pressure, liver disease, pulmonary fibrosis, thalassemia or history of smoking. At the time of analysis the median follow-up time post-dose 2 was 61 days.

Final determination of COVID-19 cases were made by an adjudication committee. Overall vaccine efficacy and efficacy by key age groups are presented in Table 2.

Table 2. Vaxzevria efficacy against symptomatic COVID-19 illness in Study D8110C00001:

N = Number of subjects included in each group; n = Number of subjects having a confirmed event; CI = Confidence Interval.
^a Symptomatic COVID-19 requiring positive Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and at least 1 respiratory sign or symptom, or at least 2 other systemic signs or symptoms, as defined in the protocol.
^b The confidence intervals were not adjusted for multiplicity.

Severe or critical symptomatic COVID-19 illness was assessed as a key secondary endpoint. Among all subjects in the per protocol set, no cases of severe or critical symptomatic COVID-19 were reported in the vaccine group compared with 8 cases reported in the placebo group. There were 9 hospitalised cases, the 8 cases that were adjudicated as severe or critical symptomatic COVID-19, and one additional case in the vaccine group. The majority of the severe or critical symptomatic COVID19 cases fulfilled only the oxygen saturation (SpO2) criterion for severe disease (≤93% on room air).

In individuals with or without prior evidence of SARS-CoV-2 infection, the vaccine efficacy of Vaxzevria (≥15 days post-dose 2) was 73.7% (95% CI: 63.1; 80.1); 76 (0.4%) vs 135 (1.5%) cases of COVID-19 for Vaxzevria (N=18,563) and placebo (N=9,031), respectively.

Participants with one or more comorbidities who received Vaxzevria (≥15 days post-dose 2) had an efficacy of 75.2% (95% CI: 64.2; 82.9) and participants without comorbidities had a vaccine efficacy of 71.8% (95% CI: 55.5, 82.1).

Analysis of pooled data from COV002 and COV003

The clinical efficacy of Vaxzevria has been evaluated based on an analysis of pooled data from two on-going randomised, blinded, controlled trials: a phase II/III study, COV002, in adults ≥18 years of age (including the elderly) in the UK; and a phase III study, COV003, in adults ≥18 years of age (including the elderly) in Brazil. The studies excluded participants with severe and/or uncontrolled cardiovascular, gastrointestinal, liver, renal, endocrine/metabolic disease, and neurological illnesses; as well as those with severe immunosuppression, pregnant women and participants with a known history of SARS-CoV-2 infection. Influenza vaccines could be administered 7 days before or after any dose of Vaxzevria. All participants are planned to be followed for up to 12 months, for assessments of safety and efficacy against COVID-19 disease.

In the pooled analysis for efficacy, participants ≥18 years of age received two doses (5 × 10¹⁰ viral particles per dose corresponding to not less than 2.5 × 10⁸ infectious units) of Vaxzevria (N=6,106) or control (meningococcal vaccine or saline) (N=6,090), administered via IM injection.

Because of logistical constraints, the interval between dose 1 and dose 2 ranged from 3 to 23 weeks (21 to 159 days), with 86.1% of participants receiving their two doses within the interval of 4 to 12 weeks (28 to 84 days).

Baseline demographics were well balanced across Vaxzevria and control treatment groups. In the pooled analysis, among the participants who received Vaxzevria with a dose interval of between 4 and 12 weeks, 87.0% of participants were 18 to 64 years old (with 13.0% aged 65 or older and 2.8% aged 75 or older); 55.1% of subjects were female; 76.2% were White, 6.4% were Black and 3.4% were Asian. A total of 2,068 (39.3%) participants had at least one pre-existing comorbidity (defined as a BMI ≥30 kg/m², cardiovascular disorder, respiratory disease or diabetes). At the time of analysis the median follow-up time post-dose 2 was 78 days.

Final determination of COVID-19 cases were made by an adjudication committee, who also assigned disease severity according to the WHO clinical progression scale. A total of 218 participants had SARS-CoV-2 virologically confirmed COVID-19 occurring ≥15 days post second dose with at least one COVID-19 symptom (objective fever (defined as ≥37.8°C), cough, shortness of breath, anosmia, or ageusia) and were without evidence of previous SARS-CoV-2 infection. Vaxzevria significantly decreased the incidence of COVID-19 compared to control (see Table 3).

Table 3. Vaxzevria efficacy against COVID-19^a:

N = Number of subjects included in each group; n = Number of subjects having a confirmed event; CI = Confidence Interval;
^a Efficacy endpoint was based on confirmed COVID-19 cases in subjects aged 18 years and over who were seronegative at baseline, who had received two doses and were on-study ≥15 days post second dose.
^b CI not adjusted for multiplicity.

Vaccine efficacy was 62.6% (95% CI: 50.9; 71.5) in participants receiving two recommended doses with any dose interval (ranging from 3 to 23 weeks), in a pre-specified analysis.

Regarding COVID-19 hospitalisation (WHO Severity grading ≥4) there were 0 (0.0%; N=5,258) cases of COVID-19 hospitalisation in participants who received two doses of Vaxzevria (≥15 days post dose 2) as compared to 8 (0.2%; N=5,210) for control, including one severe case (WHO Severity grading ≥6), reported for control. In all participants who received at least one dose, as from 22 days post dose 1, there were 0 (0.0%, N=8,032) cases of COVID-19 hospitalisation in participants who received Vaxzevria, as compared to 14 (0.2%, N=8,026), including one fatality, reported for control.

Participants who had one or more comorbidities had a vaccine efficacy of 58.3% [95% CI: 33.6; 73.9]; 25 (1.2%) vs 60 (2.9%) for Vaxzevria (N=2,068) and control (N=2,040), respectively; which was similar to the vaccine efficacy observed in the overall population.

Evidence shows protection starts from approximately 3 weeks after first dose of vaccine. A second dose should be given at a 4 to 12-week interval after the first dose (see section 4.4).

Immunogenicity after booster dose

Study D7220C00001, immunogenicity of a booster dose (third dose) following primary vaccination with Vaxzevria or an mRNA COVID-19 vaccine

D7220C00001 is a phase II/III partially double-blind, active-controlled study in which 367 participants ≥30 years old previously vaccinated with Vaxzevria and 322 participants ≥30 years old previously vaccinated with an mRNA vaccine received a single booster dose of Vaxzevria at least 90 days after receiving the second dose of their primary vaccination course. Immunogenicity was assessed in 342 participants previously vaccinated with Vaxzevria and 294 participants previously vaccinated with an mRNA vaccine, all of whom were seronegative at baseline.

The effectiveness of Vaxzevria administered as a single booster dose in participants previously vaccinated with Vaxzevria was demonstrated by evaluating non-inferiority of the immune response of pseudoneutralising antibody titres against the ancestral strain compared to that elicited by a 2-dose primary vaccination course in a subset of matched participants in study D8110C00001.

Non-inferiority for GMT ratio was demonstrated when comparing pseudoneutralising antibody titres 28 days after the booster dose to titres 28 days after the primary vaccination course (see Table 4).

Table 4. Neutralising antibody titres against the ancestral strain following booster dosing with Vaxzevria in participants previously vaccinated with Vaxzevria:

n = Number of subjects in analysis; GMT = Geometric mean neutralising antibody titre; CI = Confidence interval; GMT Ratio = Geometric mean titre ratio
^a Based on analyses from a matched cohort of participants in study D8110C00001.
^b GMT 28 days after booster dose to GMT 28 days after the second dose of the primary vaccination course.
^c Reported results have been adjusted using an ANCOVA model including fixed-effect terms for visit window, time since previous vaccination (for booster), baseline comorbidities, sex, age and a random subject effect.
^d Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the GMT ratio of the comparator group and the reference group is >0.67.

Vaxzevria was also shown to be effective in eliciting antibody responses in participants who had previously received primary vaccination with an mRNA vaccine. In these participants, a single booster dose of Vaxzevria resulted in increased humoral responses, with geometric mean fold rise (GMFR) of 3.77 (95% CI: 3.26, 4.37) in neutralising antibody titres against the ancestral strain from pre-booster to 28 days after the booster dose.

Elderly population

Study D8110C00001 assessed the efficacy of Vaxzevria in 5,508 individuals ≥65 years of age; 3,696 who received Vaxzevria and 1,812 who received placebo. The efficacy of Vaxzevria was consistent between elderly (≥65 years) and younger adult subjects (18-64 years).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Vaxzevria in one or more subsets of the paediatric population in prevention of COVID-19 (see section 4.2 for information on paediatric use).