A randomized controlled trial of heterologous ChAdOx1 nCoV-19 and recombinant subunit vaccine MVC-COV1901 against COVID-19

Abstract

Heterologous prime-boost COVID-19 vaccine strategy may facilitate mass COVID-19 immunization. We reported early immunogenicity and safety outcomes of heterologous immunization with a viral vector vaccine (ChAdOx1) and a spike-2P subunit vaccine (MVC-COV1901) in a participant-blinded, randomized, non-inferiority trial (NCT05054621). A total of 100 healthy adults aged 20-70 years having the first dose of ChAdOx1 were 1:1 randomly assigned to receive a booster dose either with ChAdOx1 (n = 50) or MVC-COV1901 (n = 50) at an interval of 4-6 or 8-10 weeks. At day 28 post-boosting, the neutralizing antibody geometric mean titer against wild-type SARS-CoV-2 in MVC-COV1901 recipients (236 IU/mL) was superior to that in ChAdOx1 recipients (115 IU/mL), with a GMT ratio of 2.1 (95% CI, 1.4 to 2.9). Superiority in the neutralizing antibody titer against Delta variant was also found for heterologous MVC-COV1901 immunization with a GMT ratio of 2.6 (95% CI, 1.8 to 3.8). Both spike-specific antibody-secreting B and T cell responses were substantially enhanced by the heterologous schedule. Heterologous boosting was particularly prominent at a short prime-boost interval. No serious adverse events occurred across all groups. The findings support the use of heterologous prime-boost with ChAdOx1 and protein-based subunit vaccines.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Consort diagram of study design.

A diagram showing trial groups and participant flow in the study (NCT05054621). Participants were randomly assigned to receive either a heterologous boost of MVC-COV1901 or a homologous booster dose of ChAdOx1. There was one screen failure (participant S30017 was unable to visit the study site in the scheduled time points) in the trial.

Fig. 2. Solicited local and systemic adverse events in the 7 days after the booster dose of the heterologous ChAdOx1/MVC-COV1901 (n = 50) and homologous ChAdOx1/ChAdOx1 (n = 50) group.

Grades 1, 2 and 3 adverse events were marked in light blue, blue and deep blue for the ChAdOx1/MVC-COV1901 group. Grades 1, 2 and 3 adverse events were marked in light purple, purple and deep purple for the ChAdOx1/ChAdOx1 group. The higher the grade, the more severe the adverse event. Source data are provided as a Source Data file.

Fig. 3. Comparison of antibody titers between heterologous ChAdOx1/MVC-COV1901 (n = 50) and homologous ChAdOx1/ChAdOx1 (n = 50) groups prior to and after booster vaccination.

a Neutralizing antibody titers measured by ELISA-based method. The data from 15 human convalescent serum samples collected at day 28 ± 3 after diagnosis is shown for comparison (grey bar). The values in international units per milliliter (IU/mL) are provided. Data are presented as geometric mean ±95% confidence intervals. The significance between two groups was determined using t test (two-tailed). Comparisons of antibody titers, Day 0, P = 0.7900; Day 10 ± 3, P < 0.0010; Day 28 ± 3, P < 0.0010. b Neutralizing antibody titers against wild-type Wuhan-1 and Delta variant measured by plaque reduction neutralization assay for day 28 ± 3 serum. The half-maximal neutralization titer (NT50) values are provided. Data are presented as geometric mean ±95% confidence intervals. The significance between two groups was determined using t test (two-tailed). Comparisons of antibody titers, Wuhan strain, P < 0.0010; Delta strain, P < 0.0010. c Binding-antibody titers in ELISA Unit (EU) against spike S1 protein and receptor-binding domain (RBD). Comparisons of anti-S1 titers, Day 0, P = 0.5260; Day 10 ± 3, P < 0.0010; Day 28 ± 3, P < 0.0010. Comparisons of anti-RBD titers, Day 0, P = 0.4850; Day 10 ± 3, P = 0.0020; Day 28 ± 3, P < 0.0010. Data are presented as geometric mean ±95% confidence intervals. The significance between two groups was determined using t test (two-tailed). **P  <  0.01, ***P  <  0.001, NS not significant. Source data are provided as a Source Data file.

Fig. 4. Comparisons of antibody titers of short (4–6 weeks, n = 25) and long (8–10 weeks, n = 25) vaccine dosing intervals.

Neutralizing antibody titers were measured by ELISA-based method. The values in international units per milliliter (IU/mL) are provided. Data are presented as geometric mean ±95% confidence intervals. The significance between two dose intervals was determined using t test (two-tailed). Comparisons of antibody titers for the heterologous MVC-COV1901 group, Day 0, P = 0.2720; Day 10 ± 3, P = 0.0250; Day 28 ± 3, P = 0.0050. Comparisons of antibody titers for the homologous ChAdOx1 group, Day 0, P = 0.0270; Day 10 ± 3, P = 0.0480; Day 28 ± 3, P = 0.2630. *P  <  0.05, **P  <  0.01, NS not significant. Source data are provided as a Source Data file.

Fig. 5. Antibody-secreting B cell response to SARS-CoV-2 spike is detected in recipients after the booster dose.

a Representative ELISpot from one ChAdOx1/MVC-COV1901 recipient (S069) and one ChAdOx1/ChAdOx1 recipient (S073). b IgG, IgM, IgA-secreting ASCs frequencies to spike prior to, at day 10 ± 3, and day 28 ± 3 after the booster dose in ChAdOx1/MVC-COV1901 (n = 49) and ChAdOx1/ChAdOx1 (n = 45) groups. The mean frequency of spike-specific ASCs response and its standard deviation at each time point is shown in the figure. Each point represents a single recipient and red line represents the mean. The significance between two groups was determined using a Mann–Whitney test (two-tailed). Day 10 ± 3 IgG, P = 0.0007; Day 10 ± 3 IgM, P = 0.7674; Day 10 ± 3 IgA, P = 0.0010. c The relationship between day 10 ± 3 IgG-secreting ASCs response and serological antibody response at day 10 ± 3 (n = 94) and day 28 ± 3 (n = 94). Antibody titer was measured using a SARS-CoV-2 surrogate virus neutralization test and represented as international units (IU) per mL of serum. The correlation was determined using simple linear regression. d Comparison of day 10 ± 3 ASCs response in short (4-6 weeks, n = 24 in ChAdOx1/MVC-COV1901 group, n = 20 in ChAdOx1/ChAdOx1 group) and long (8–10 weeks, n = 25 in ChAdOx1/MVC-COV1901 group, n = 25 in ChAdOx1/ChAdOx1 group) vaccine dosing intervals. The mean frequency of spike-specific ASCs response and its standard deviation is shown in the figure. Each point represents a single recipient and red line represents the mean. The significance between vaccine dosing intervals was determined using one-way ANOVA with post hoc Dunn’s multiple comparison test. IgG, P = 0.0004, post hoc ChAdOx1/MVC-COV1901 short vs ChAdOx1/MVC-COV1901 long, P = 0.0144; ChAdOx1/MVC-COV1901 short vs ChAdOx1/ChAdOx1 short, P = 0.0004; ChAdOx1/MVC-COV1901 short vs ChAdOx1/ChAdOx1 long, P = 0.0046. IgM, P = 0.4917. IgA, P = 0.0657. *P  <  0.05, **P  <  0.01, ***P  <  0.001, NS not significant, ASC antibody-secreting B cell. Source data are provided as a Source Data file.

Fig. 6. T cell response to SARS-CoV-2 spike is present in recipients prior to and after the booster dose.

a Representative ELISpot from one ChAdOx1/MVC-COV1901 recipient (S062) and one ChAdOx1/ChAdOx1 recipient (S071) against spike (pools 1 and 2), with DMSO as negative control and PHA as positive control. b Total spike-specific T-cell responses (sum of S1 and S2 subunit responses, mean ± standard deviation) prior to, at day 10 ± 3, and day 28 ± 3 after the booster dose in ChAdOx1/MVC-COV1901 (n = 49) and ChAdOx1/ChAdOx1 (n = 45) groups. Each point on violin plot represents a single recipient and black line represents the median. The significance was determined using one-way ANOVA with post hoc Dunn’s test. ChAdOx1/MVC-COV1901, Day 0 vs Day 10 ± 3, P < 0.0001; Day 0 vs Day 28 ± 3, P = 0.0486. ChAdOx1/ChAdOx1, Day 0 vs Day 10 ± 3, P > 0.9999; Day 0 vs Day 28 ± 3, P > 0.9999. The significance between two groups was determined using a Mann–Whitney test (two-tailed). Day 0, P = 0.7022; Day 10 ± 3, P = 0.0039; Day 28 ± 3, P = 0.0053. c Summary data of day 28 ± 3 T cell response in vaccine recipients according to spike peptide pools (mean±standard deviation). The significance was determined using one-way ANOVA with post hoc Dunn’s test. S1 pool comparison, P = 0.0345; S2 pool comparison, P = 0.0334. d The fold change of total spike-specific T-cell responses on day 10 ± 3 (left panel) and 28 ± 3 (right panel) relative to the response prior to the booster dose in short (4–6 weeks, n = 24 in ChAdOx1/MVC-COV1901 group, n = 20 in ChAdOx1/ChAdOx1 group) and long (8–10 weeks, n = 25 in ChAdOx1/MVC-COV1901 group, n = 25 in ChAdOx1/ChAdOx1 group) vaccine dosing intervals (mean±standard deviation). Each point represents a single recipient and red line represents the mean. The significance was determined using one-way ANOVA with post hoc Dunn’s test. Day 28 ± 3, P = 0.0234, post hoc ChAdOx1/MVC-COV1901 long vs ChAdOx1/ChAdOx1 short, P = 0.0273. *P  <  0.05, **P  <  0.01, ****P  <  0.0001, NS not significant, DMSO dimethylsulfoxide, PHA Phytohaemagglutinin, s.f.c. spot-forming cells. Source data are provided as a Source Data file.