Timing of Booster Dose and Efficacy of ChAdOx1 nCoV-19 Vaccine

Quick Takes

  • In this updated pooled analysis of three randomized trials of the ChAdOx1 nCoV-19 vaccine by Oxford/AstraZeneca, the overall effectiveness of the vaccine in reducing the risk of symptomatic COVID-19 was 66.7%.
  • Antibody responses were more than two-fold higher after a prime-boost interval of 12 weeks compared to an interval of <6 weeks, and efficacy was higher after longer prime-boost interval (81.3% at ≥12 weeks compared to 55.1% at <6 weeks).
  • The implications are enormous for vaccine distribution, as delaying the booster dose for 3 months would support the rapid expansion of first-dose vaccine administration while additional doses are manufactured.

Study Questions:

Does the efficacy of the ChAdOx1 nCoV-19 vaccine in reducing the risk of symptomatic coronavirus disease 2019 (COVID-19) vary depending on the interval between the initial dose (prime) and the booster dose?

Methods:

The ChAdOx1 nCoV-19 vaccine (AZD1222) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structural surface glycoprotein antigen (spike protein; nCoV-19) gene. This study provides an updated pooled analysis of four ongoing randomized trials of the ChAdOx1 nCoV-19 vaccine done across three countries (United Kingdom [UK], Brazil, and South Africa), including 17,178 participants who were randomized 1:1 to receive the vaccine or a control product. Participants in the intervention group received two doses of the vaccine ≥4 weeks apart. The primary outcome was virologically confirmed, symptomatic COVID-19 occurring >14 days after the second dose. Events were considered for the single-dose efficacy analysis if occurring 21 days after the dose. This analysis provides an updated efficacy of a two-dose vaccination strategy in addition to examining differences in efficacy and immunogenicity between shorter and longer prime-boost intervals.

Results:

A total of 17,178 participants met the inclusion criteria for the primary analysis, 8,597 of whom received two doses of ChAdOx1 nCoV-19 and 8,581 of whom received two doses of control product. Most patients were 18-55 years of age. There were 332 participants who met the primary endpoint: 84 (1.0%) cases among 8,597 participants in the vaccine arm and 248 (2.9%) cases among 8,581 participants in the control group, resulting in an overall vaccine efficacy of 66.7% (95.8% confidence interval [CI], 57.4-74.0). Three-month efficacy after a single dose was 76.0% (95% CI, 59.3-85.9). Antibody levels were maintained with minimal waning for 3 months after a single dose, and were two-fold higher in those who received the second dose at ≥12 weeks compared to <6 weeks. Efficacy was higher in the subset who received the second dose at ≥12 weeks (81.3%, n = 2,038) compared to the subset who received the second dose at <6 weeks (55.1%, n = 3,890).

Conclusions:

Longer intervals between the initial ChAdOx1 nCoV-19 vaccine dose and the booster dose are associated with a higher antibody response and may be more efficacious at preventing symptomatic COVID-19 than shorter intervals.

Perspective:

This updated pooled analysis of four phase 3 clinical trials of the Oxford/AstraZeneca ChAdOx1 nCoV-19 vaccine confirms the initial interim analysis showing a two-dose efficacy of approximately 75% in preventing symptomatic COVID-19. The most important contribution of this updated report is in the study of the variation in immunogenicity and efficacy based on the prime-boost interval. The antibody response of a single dose appears to be maintained up to 3 months, with the subgroup of participants who received the booster dose at or after 3 months having a lower incidence of COVID-19 compared to those who received the dose at <6 weeks. While hypothesis-generating at best given the post hoc exploratory nature of this secondary analysis, the findings suggest that delaying the second booster dose to 3 months could be an acceptable strategy. The implications are enormous for vaccine distribution, supporting the rapid expansion of first-dose vaccine administration while additional doses are manufactured; a strategy adopted by the UK in its highly debated roll-out. The UK experience will be invaluable in determining the true efficacy of this strategy. Whether the immune response and efficacy of other COVID-19 vaccines behave similarly remain to be seen.

Clinical Topics: Prevention

Keywords: Antibody Formation, Coronavirus, COVID-19, Immunization, Secondary, Membrane Glycoproteins, Pan troglodytes, Primary Prevention, severe acute respiratory syndrome coronavirus 2, Spike Glycoprotein, Coronavirus, Vaccination, Vaccines


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