. 2021 Oct 11;9(10):1163. doi: 10.3390/vaccines9101163

Table 2.

Studies of heterologous ChAdOx1-S with mRNA vaccination.

Reference	Country	Design	Interval between Doses	Intervention (1st/2nd Dose)	Results
Johan N. et al., 2021 [35]	Sweden	An open, multicenter phase IV study	9–12 weeks	Homologous vaccine group: ChAdOx1-S/ChAdOx1-S (n = 37, 28- to 62-year-old) Heterologous vaccine group: ChAdOx1-S/mRNA-1273 (n = 51, 23- to 59-year-old)	S-specific and RBD-specific IgG geometric mean titers At the day of the 2nd dose inoculation, the similar titer of S-specific and RBD-specific IgG between two groups At D7 to D10 after 2nd dose inoculation, S-specific and RBD-specific IgG titers in the ChAdOx1-S/mRNA-1273 were separately 115-fold and 125-fold of that on the day of the 2nd dose inoculation, and that was 5-fold in the ChAdOx1-S/ChAdOx1-S At D30 after 2nd dose inoculation, S-specific and RBD-specific IgG titers in two groups were the same with that on D7 to D10 time point. Neutralization antibody against wild type SARS-CoV-2 At the day of 2nd dose inoculation, the titer of ID₅₀ was similar between two groups At D7 to D10 after 2nd dose inoculation, the titer of ID₅₀ in the ChAdOx1-S/mRNA-1273 was 20-fold of that on the day of 2nd dose inoculation and it was 2-fold in the ChAdOx1-S/ChAdOx1-S At D30 after 2nd dose inoculation, the titer of ID₅₀ in two groups was 1.6 to 1.7-fold of that on D7 to D10 time point, but it was not significant Neutralization antibody against B.1.351, Beta variant SARS-CoV-2 At the D7 to D10 after 2nd dose inoculation, the ChAdOx1-S/mRNA-1273 had induced the antibodies that could neutralize the B.1.351, Beta variant SARS-CoV-2, but the ChAdOx1-S/ChAdOx1-S could not induce potent antibodies against this variant Adverse events (on the D7 to D10 after 2nd dose inoculation) No serious adverse events were reported in two groups The incidence of systemic adverse events such as fever, headache, chills and injection site pain, was frequently found in the ChAdOx1-S/mRNA-1273 than that in the ChAdOx1-S/ChAdOx1-S The grade of adverse events was not statistically significant different between two groups
Robert, H.S. et al., 2021 [33,34,36]	UK	A single-blind, randomized, multicenter phase II study	4 weeks	Homologous vaccine group (50- to 69-year-old): ChAdOx1-S/ChAdOx1-S (n = 115); BNT162b2/BNT 162b2 (n = 110) Heterologous vaccine group (50- to 69-year-old): ChAdOx1-S/BNT162b2 (n = 110); BNT162b2/ChAdOx1-S (n = 114)	Adverse events No serious adverse events reported in all groups within 7 days after inoculation The systemic adverse events were more frequently found in the heterologous vaccine groups than that in their homologous vaccine groups within 2 days after inoculation
Alberto, M.B. et al., 2021 [34,37]	Spain	An open-label, randomized, controlled multicenter phase II study	8–12 weeks	Without homologous vaccine group, only 1 dose of ChAdOx1-S (n = 226, 18- to 60-year-old): Heterologous vaccine group (18- to 60-year-old): ChAdOx1-S/BNT162b2 (n = 451)	S-specific and RBD-specific IgG geometric mean titers At the day of 2nd dose inoculation, the similar titer of S-specific and RBD-specific IgG between two groups The titer of S-specific and RBD-specific IgG in the 1st dose of ChAdOx1-S on the day of 2nd dose inoculation, which was similar to that on D7 and D14 after inoculation At D7 and D14 after 2nd dose inoculation, both S-specific and RBD-specific IgG titers in the ChAdOx1-S/BNT162b2 were significantly higher than that in the 1st dose of ChAdOx1-S Neutralization antibody against pseudovirus-SARS-CoV-2 At the day of 2nd dose inoculation, PVNT50 was similar between two groups At D14 after 2nd dose inoculation, PVNT50 in the ChAdOx1-S/BNT162b2 were 45-fold of that in the 1st dose of ChAdOx1-S S-specific T cell immune response At the day of 2nd dose inoculation, production of IFN-γ was similar between two groups At the D14 after 2nd dose inoculation, production of IFN-γ in the ChAdOx1-S/BNT162b2 was significantly higher than in the 1st dose of ChAdOx1-S Adverse events No serious adverse events were reported in heterologous vaccine group Incidence of systematic adverse events were more than others in ChAdOx1-S/BNT162b2 within D7 after 2nd dose of inoculation There was no data regarding the difference in the incidence of adverse events between the two group
Tina S. et al., 2021 [41]	Germany	Observation study	9–12 weeks: ChAdOx1-S/ChAdOx1-S; ChAdOx1-S/BNT162b2 or mRNA-1273 3–6 weeks: BNT162b2/BNT162b2 or mRNA-1273/mRNA-1273	Homologous vaccine group: ChAdOx1-S/ChAdOx1-S (n = 55, 36- to 61-year-old); BNT162b2/BNT162b2 or mRNA-1273/mRNA-1273 (n = 62, 29- to 52-year-old) Heterologous vaccine group: ChAdOx1-S/BNT162b2 or mRNA-1273 (n = 96, 30- to 59-year-old)	S-specific IgG geometric mean titers: At the D14 after 2nd dose inoculation, the titer of S-specific IgG was similar between ChAdOx1-S/BNT162b2 or mRNA-1273 and 2 dose of BNT162b2 or mRNA-1273, that was significantly higher than that in the ChAdOx1-S/ChAdOx1-S Neutralization antibody against SARS-CoV-2 by surrogate virus neutralization test At the D14 after 2nd dose inoculation, the percentage inhibition of neutralization antibody was similar between ChAdOx1-S/BNT162b2 or mRNA-1273 and 2nd dose of BNT162b2 or mRNA-1273, that was significantly higher than that in the ChAdOx1-S/ChAdOx1-S S-specific T cell immune response: At the D14 after 2nd dose inoculation, percentage of CD69+ IFN-γ+ CD4+ T cells was similar between ChAdOx1-S/BNT162b2 or mRNA-1273 and 2nd dose of BNT162b2 or mRNA-1273, that was significantly higher than that in the ChAdOx1-S/ChAdOx1-S The percentage of CD69+ IFN-γ+ CD8+ T cells was significantly higher than that in both ChAdOx1-S/ChAdOx1-S and 2nd dose of BNT162b2 or mRNA-1273 Adverse events (within D7 after 2nd inoculation): No serious adverse events were reported in heterologous vaccine group The incidence of adverse events in the ChAdOx1-S/BNT162b2 or mRNA-1273 was similar to that in the 2 doses of BNT162b2 or mRNA-1273, but more than that in the 2 doses of ChAdOx1-S The incidence of adverse events in the ChAdOx1-S/BNT162b2 was similar to that in the ChAdOx1-S prime
Rüdiger G. et al., 2021 [38]	Germany	Clinical study	8 weeks	Homologous vaccine group: BNT162b2/BNT162b2 (n = NR, 25-to 55-year-old) Heterologous vaccine group: ChAdOx1-S/BNT162-b2 (n = 26, 25- to 46- year-old)	S-specific IgG titer: At the D14–19 after 2nd dose inoculation, this titer in the ChAdOx1-S/BNT162b2 were separately significantly higher than that at the day of 2nd dose inoculation and that in the 2 doses of BNT162b2 at D13–15 after 2nd dose inoculation Neutralization antibody against pseudovirus-wild type-SARS-CoV-2 At the D14–19 after 2nd dose inoculation, the PVNT50 in the ChAdOx1-S/BNT162b2 were separately significantly higher than that at the day of 2nd dose inoculation and that in the 2 doses of BNT162b2 at D13–15 after 2nd dose inoculation Neutralization antibody against pseudovirus-variant-SARS-CoV-2 PVNT50 against alpha- and beta-SARS-CoV-2 in in the ChAdOx1-S/BNT162b2 at D14–19 after 2nd dose inoculation, was separately higher than that in the 2 doses of BNT162b2 at D13–15 after 2nd dose inoculation, but the PVNT50 against delta-SARS-CoV was similar between two groups S-specific T cell immune response: A significantly high percentage of S-specific IFN-γ+CD4 or CD8 T cells the ChAdOx1-S/BNT162b2 at the D6–11 and D14–19 after 2nd dose inoculation in comparison to that at D2 before 1st dose inoculation There was no data regarding the difference on S-specific T cell immune response between two groups Adverse events (lasting than D1 after boost): No serious adverse events were reported in heterologous vaccine group There is no data regarding the difference in the incidence of adverse events between the two groups
Xin Xue L. et. al., 2021 [39]	UK	A single blinded, randomized, multicenter, phase II, non-inferiority study	4 weeks	Homologous vaccine group (50- to 69-year-old): ChAdOx1-S/ChAdOx1-S (n = 112); BNT162b2/BNT162b2 (n = 110) Heterologous vaccine group (50- to 69-year-old): ChAdOx1-S/BNT162b2 (n = 110); BNT162b2/ChAdOx1-S (n = 114)	S-specific IgG geometric mean titers: At D28 after 2nd dose inoculation, there was a similar titer between the ChAdOx1-S/BNT162b2 and BNT162b2/BNT162b2, but that in ChAdOx1-S/BNT162b2 were significantly higher than that in ChAdOx1-S/ChAdOx1-S and BNT162b2/ChAdOx1-S Neutralization antibody against pseudovirus-wild type-SARS-CoV-2: At D28 after 2nd dose inoculation, there was a similar PVNT₅₀ between the ChAdOx1-S/BNT162b2 and BNT162b2/BNT162b2, but that in ChAdOx1-S/BNT162b2 were significantly higher than that in ChAdOx1-S/ChAdOx1-S and BNT162b2/ChAdOx1-S S-specific T cell immune response: At D28 after 2nd dose inoculation, the number of IFN-γ+T cell per 10⁶ PBMC in ChAdOx1-S/BNT162b2 was more than that in ChAdOx1-S/BNT162b2, BNT162b2/BNT162b2 and BNT162b2/ChAdOx1-S Adverse events: Within D28 after 2nd dose inoculation, the incidence of systemic adverse events was increased in heterologous vaccine group as compared to their homologous vaccine group, but no significant difference between those vaccine schedules Within D28 after 2nd dose inoculation, there were four serious adverse events across all groups, but not related to vaccine immunization
David H. et al., 2021 [42]	Germany	Prospective study	3 weeks: BNT162b2/BNT162b2 10–12 weeks: ChAdOx1-S/ChAdOx1-S, ChAdOx1-S/BNT162b2	Homologous vaccine group: ChAdOx1-S/ChAdOx1-S (n = 38, 33- to 59-year-old); BNT162b2/BNT162b2 (n = 174, 29- to 43-year-old) Heterologous vaccine group: ChAdOx1-S/BNT162-b2 (n = 104, 29- to 51-year-old)	S1-specific and RBD-specific IgG signal-to cutoff- ratio: At D21–28 after 2nd dose inoculation, the ratio of S1-specific IgG in the ChAdOx1-S/BNT162b2 was more than that in all homologous vaccine groups, but no significant difference At D21–28 after 2nd dose inoculation, the ratio of RBD-specific IgG in ChAdOx1-S/BNT162b2 was similar to that in BNT162b2/BNT162b2 and slightly more than that in the ChAdOx1-S/ChAdOx1-S Index of S1-specific IgG avidity: At D21–28 after 2nd dose inoculation, the index of S1-specific IgG avidity in the ChAdOx1-S/BNT162b2 was significantly higher than that in all homologous vaccine groups Neutralization antibody against pseudovirus-variant-SARS-CoV-2 At D21–28 after 2nd dose inoculation, PVNT₅₀ against alpha- and beta- SARS-CoV-2 in the ChAdOx1-S/BNT162b2 was significantly higher than that in all homologous vaccine groups S1-specific T cell immune response: At the D21–28 after 2nd inoculation, the production of IFN-γ in the ChAdOx1-S/BNT162b2 was significantly higher than that in in all homologous vaccine groups Adverse events (within 24 h after 2nd dose inoculation): No serious adverse events were reported across all groups The incidence of systemic adverse event in the ChAdOx1-S/BNT162b2 was slightly more than in ChAdOx1-S/ChAdOx1-S and less than that in BNT162b2/BNT162b2 and ChAdOx1-S prime
Gram M.A. et al. [40]	Denmark	Clinical study	82 days	Heterologous vaccine group: ChAdOx1-S/BNT162b2 (n = 88,050) ChAdOx1-S/mRNA-1273 (n = 44,501) Median age of 45 and 46 years at the first and second dose	A reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine. The vaccine effectiveness (VE) against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88%. The VE of ChAdOx1/mRNA is similar to the two doses of the BNT162b2 mRNA vaccine. No COVID-19 related hospitalizations were observed after the second dose. No COVID-19 related deaths were observed after neither the first dose ChAdOx1 nor the ChAdOx1/mRNA vaccine schedule.

S, spike protein; RBD, receptor-binding domain; ID₅₀, 50% inhibitory dilution; PVNT₅₀, 50% of pseudovirus neutralization titer; NR, not reported; S1, S1 domain of spike protein.