Heterologous COVID-19 Vaccine Priming Schedules Elicit Persistent Immunity

Heterologous COVID-19 vaccination remained more immunogenic over time than homologous vaccination in ChAdOx1-primed patients, suggesting the viability of heterologous priming schedules in future pandemics.

Results of a study published in the Journal of Infection suggest that heterologous COVID-19 vaccine priming schedules are associated with persistent immune responses for up to 6 months, suggesting mixed schedules may be a viable vaccination strategy for future pandemics.

The Com-COV2 (ISRCTN:27841311) study was a single-blinded trial conducted in England in 2021. Eligible patients (N=1072) were aged 50 years and older with no history of SARS-CoV-2 infection who had received a single priming dose of either the ChAdOx1 or BNT162b2 vaccines. Patients were randomly assigned 1:1:1 to receive a second dose of the same vaccine, mRNA-1273, or NVX-CoV2373 between weeks 8 and 12. The primary outcome was immunologic response up to day 196.

Among patients included in the analysis, 54 were primed with ChAdOx1 and 532 were primed with BNT162b2.

Following receipt of the second vaccine dose, the anti-spike immunoglobulin (Ig)G geometric mean concentration (GMC) at day 196 was 3588 enzyme-linked immunosorbent assay laboratory units (ELU)/mL for BNT162b2 plus mRNA-1273 recipients. Anti-spike IgG GMCs among other priming combinations were 3191 ELU/mL for ChAdOx1 plus mRNA-1273 recipients; 2281 ELU/mL for BNT162b2 plus BNT162b2 recipients; 1334 ELU/mL for BNT162b2 plus NVX-CoV2373 recipients; 1052 ELU/mL for ChAdOx1 plus NVX-CoV2373 recipients; and 494 ELU/mL for ChAdOx1 plus ChAdOx1 recipients.

The magnitude of anti-spike IgG waning was initially slower for ChAdOx1 plus ChAdOx1 recipients compared with both ChAdOx1 plus mRNA-1273 recipients and ChAdOx1 plus NVX-CoV2373 recipients until day 112. After day 112, this difference in waning speed was attenuated. In addition, magnitude of waning was initially slower for BNT162b2 plus NVX-CoV2373 recipients compared with BNT162b2 plus BNT162b2 recipients until day 56 but was reduced thereafter. Waning speeds were similar between BNT162b2 plus BNT162b2 recipients and BNT162b2 plus mRNA-1273 recipients.

It is not clear, yet, whether one combination of vaccine platforms may hold clinically significant advantages over any other combination.

Live virus neutralization assays indicated similar outcomes among most mixed vaccine combinations, though the combination of BNT162b2 plus NVX-CoV2373 was associated with a lower response compared with BNT162b2 plus BNT162b2.

Mixed effects linear regression was used to identify covariates that significantly affected humoral immunogenicity across mixed vaccine schedules. For patients primed with ChAdOx1 and BNT162b2, significant covariates included anti-spike IgG levels at receipt of the second vaccine dose and BMI. However, age and time between receipt of the first and second vaccine dose were significant covariates for BNT162b2-primed recipients, whereas patient sex was significant for ChAdOx1-primed recipients.

A total of 756 adverse events occurred among 436 patients. Overall, 34 patients in each study arm tested positive for SARS-CoV-2 infection, 1 of whom required hospitalization but did not receive invasive ventilation.

This study was limited as the primary vaccine dose was not randomly administered. Other limitations include a greater number comorbidities among BNT162b2-primed patients and the lack of follow-up beyond 6 months.

“It is not clear, yet, whether one combination of vaccine platforms may hold clinically significant advantages over any other combination,” the researchers noted. “However, heterologous priming schedules might be considered, to ease logistical constraints, as a viable option sooner in future pandemics,” they concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Shaw RH, Greenland M, Stuart ASV, et al. Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study – a single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines Heterologous COVID vaccination immune persistence: Com-COV2. J Infect. Published online April 5, 2023. doi:10.1016/j.jinf.2023.03.027