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Safety, Reactogenicity, and Immunogenicity of Homologous and Heterologous Prime-Boost immunization with ChAdOx1-nCoV19 and BNT162b2: A Prospective Cohort Study

Our take —

This was a prospective cohort study conducted in Germany. Researchers compared the immunological responses as well as local and systematic reactions between two groups: the homologous group (i.e., two doses, three weeks apart, of the same vaccine formulation [BNT162b2 by Pfizer-BioNTech]) and the heterologous group (i.e., two doses of different vaccine formulations 10-12 weeks apart [first ChAdOx1 by AstraZeneca and then BNT162b2]). As shown in other studies, participants’ B-cell immune responses were significantly higher after the 1st dose with BNT162b2 compared to ChAdOx1. However, following the second dose of BNT162b2, the heterologous group had comparable B-cell immune responses and slightly higher T-cell immune responses, versus the homologous group. Both groups experienced similar local reactions after their first and second doses. Systemic reactions were more common after the first dose of ChAdOx1 vs. BNT162b2 but less common in the heterologous group after the second dose with BNT162b2. This study highlights the laboratory evidence of efficacy and safety assurance of heterologous immunization with ChAdOx1 followed 10-12 weeks later by BNT162b2, especially for females who are more likely to have rare thromboembolic adverse event following two doses with ChAdOx1. These results are limited by a relatively small sample size and lacked an evaluation of the clinical effectiveness of heterologous immunization.

Study design

Prospective Cohort

Study population and setting

This was a prospective cohort study conducted in Germany that included healthcare workers who received either (1) homologous immunization with two doses, three weeks apart, of BNT162b2 (Pfizer-BioNTech) vaccine or (2) heterologous immunization with an initial dose of ChAdOx1-nCoV19 (AstraZeneca) vaccine followed 10-12 weeks later by BNT162B2. Baseline demographic data were collected at the study enrollment. Anti-nucleocapsid antigen was measured at enrollment to exclude participants with prior infection with SARS-CoV-2. B-Cell immunity against SARS-CoV-2 was quantified by measuring anti-receptor binding domain and anti-S1 antibodies using enzyme-linked immunosorbent assay (ELISA), and T-cell immunity by measuring INF-Gamma induced by S1 peptide antigen. High serum antibody avidity was defined as antibodies with more than 60% avidity. These B-cell and T-cell responses were compared between subsets of both groups, who were matched on age and sex. The proportion of participants who had local and systemic reactions after 1st (prime) and 2nd (booster) doses were captured by asking the participants to fill electric questionnaires on days 1, 3, 5, and 7 after every vaccination.

Summary of Main Findings

One hundred eighty-nine participants received two doses of BNT162B2 vaccine, three weeks apart (homologous boost group), and 110 participants received heterologous immunization with ChAdOx1 vaccine followed by BNT162B2 vaccine with a median time of 71 days between doses (heterologous boost group). The median ages of the groups were 35 and 38 years, respectively. The homologous group was 55% women vs. 78% in the heterologous group.

After vaccination with the first dose, 67% (95% CI: 57 – 76%) of those who received BNT162B2 had anti-S1 antibodies compared to 28% (95% CI: 18 – 40%) in the ChAdOx1 group, with a statistically significant difference. However, after the second dose with BNT162b2, all patients had anti-SARS-COV-2 S1 antibodies. Similarly, after the first dose, 95% of the homologous group had neutralizing antibodies compared to 84% in the heterologous group, with a statistically significant difference, but 100% and 99% had neutralizing antibodies after the second dose, respectively.

High serum antibody avidity was not detected after the first dose of vaccine in either group. Avidity is the overall strength of connection between an antibody and its attachment site on a disease-causing microbe. After the second dose, high serum antibody avidity was detected in 100% (95% CI: 94 – 100%) of participants in the heterologous group and 90% (95% CI 74 – 97%) in the homologous group. The median level for the interferon gamma assay was statistically higher in the heterologous group (2.25 AU) than the homologous group (1.67 AU). Across groups, there were no noticeable differences in local reactions to either the first or second dose of vaccine. However, systemic reactions were more common after the first dose of ChAdOx1 in the heterologous group vs. the first dose of BNT162b2 in the homologous group, but less common after the second dose in the heterologous group.

Study Strengths

B-cell and T-cell immune response were measured in subsets in both groups who were matched on age and sex and at comparable intervals following vaccine administration in both groups, which strengthen the comparability between the study groups. Also, data were collected prospectively which minimized the chance of information or recall bias.


Only subsets of both cohorts had serum testing for B-cell and T-cell immune responses, and matching between both cohorts were based only on age and sex. This could have resulted in selection bias if subjects in both groups were different in a way that that could affect their immune response to the vaccine (e.g., being immunocompromised). Also, local and systemic reactions were measured by soliciting response through direct questionnaires instead of observation. Since the study was unmasked as well, participants might have been influenced to be more or less observant to their reactions, based on their prior knowledge of their specific vaccine’s side effects. Furthermore, there was not a comparison group consisting of heterologous immunization with a 3-week interval between doses, which makes it difficult to discern whether the heterologous immunization or difference in timing was responsible for these results.

Value added

This is the first study to examine B-cell and T-cell immune responses as well as local and systematic reactions between heterologous (ChAdOx1 then BNT162b2) and homologous (BNT162b2 for both doses) immunization groups. Since females have been reported to be more prone to rare but serious thromboembolic events following ChAdOx1 vaccination, this study provides strong laboratory data for the efficacy and safety of heterologous immunization, at least at the short run.

This review was posted on: 26 July 2021