Heterologous vs. Homologous Prime-Boost Schedules for COVID-19 Vaccines

Quick Takes

  • The heterologous and homologous schedules of ChAd and BNT can induce robust immune responses with a 4-week prime-boost interval.
  • Overall, these results support flexibility in deploying mRNA and viral vectored vaccines, subject to supply and logistical considerations.
  • There is a need for additional research on other mixed schedules with different prime-boost intervals, especially for vaccines in low-income and middle-income countries to optimize vaccination rates.

Study Questions:

What is the safety and immunogenicity of heterologous schedules with the adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca [ChAd]) and the messenger RNA (mRNA) vaccine (BNT162b2, Pfizer-BioNTech [BNT])?

Methods:

The investigators conducted Com-COV, a participant-blinded, randomized, noninferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged ≥50 years with no or well-controlled comorbidities and no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by laboratory confirmation were eligible and were recruited at eight sites across the United Kingdom. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n = 100) was enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval.

The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered noninferior to the approved homologous schedules if the lower limit of the one-sided 97.5% confidence interval (CI) of the geometric mean ratio of these comparisons was >0.63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.

Results:

Between February 11 and February 26, 2021, 830 participants were enrolled and randomized, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57.8 years (standard deviation, 4.7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post-boost, the geometric mean concentration of SARS-CoV-2 anti-spike immunoglobulin G (IgG) in ChAd/BNT recipients (12,906 ELU/ml) was noninferior to that in ChAd/ChAd recipients (1392 ELU/ml), with a GMR of 9.2 (one-sided 97.5% CI, 7.5 to ∞). In participants primed with BNT, they did not show noninferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/ml) against the homologous schedule (BNT/BNT, 14,080 ELU/ml), with a GMR of 0.51 (one-sided 97.5% CI, 0.43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunization.

Conclusions:

The authors concluded that the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against coronavirus disease 2019 (COVID-19) disease and hospitalization.

Perspective:

This randomized study reports that the heterologous and homologous schedules of ChAd and BNT can induce robust immune responses with a 4-week prime-boost interval. Furthermore, the cellular and humoral responses of the two heterologous vaccine schedules at 28 days after the boost dose are no lower than those of the ChAd/ChAd schedule, which has shown to be highly effective in preventing severe COVID-19 disease, and no safety concerns were raised. Overall, these results support flexibility in deploying mRNA and viral vectored vaccines, subject to supply and logistical considerations, and underscore the need for additional research on other mixed schedules with different prime-boost intervals, especially for vaccines being deployed in low-income and middle-income countries.

Clinical Topics: Prevention

Keywords: Adenoviridae, Coronavirus, COVID-19, COVID-19 Vaccines, Enzyme-Linked Immunosorbent Assay, Genetic Vectors, Hematologic Tests, Immunity, Immunoglobulin G, Primary Prevention, RNA, Messenger, SARS-CoV-2, Vaccination, Viral Vaccines


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