Prime-Boost COVID-19 Vaccination against SARS-CoV-2: Comparison
Please note this is a comparison between Version 1 by Yu-Chang Tyan and Version 3 by Camila Xu.

The types of these vaccines include two recombinant adenovirus vaccines (ChAdOx1-S and Ad26.COV2-S), one heterologous recombinant adenovirus vaccine (Gam-COVID-Vac), two mRNA vaccines (BNT162b2 and mRNA-1273), two inactivated virus vaccines (BBIBP-CorV and CoronaVac), and one recombinant protein vaccine (NVX-CoV2373).

  • SARS-CoV-2
  • COVID-19
  • heterologous
  • vaccine safety
  • T-cell response

1. Introduction

According to Table 1, for full immunization with most vaccines (excluded from Ad26.COV2-S and Gam-COVID-VaC), people need to be inoculated with two doses of the same vaccines (i.e., homologous vaccination, homologous vaccine regimen, or homologous prime-boost schedules) with an interval of 14 days to three months. As of 26 September 2021, only 32.86% of the world was fully immunized with the COVID-19 vaccine [1][25]. Vaccine shortage delays the schedule for the second dose of homologous vaccination and postpones the achievement of global herd immunity.
Table 1.
List of valid vaccines for COVID-19.
Vaccine Name Developer Country Manufacturer Vaccine Type Storage Temperature/Shelf Life Number of Doses Interval between Doses Vaccine Efficacy/Age (y) Serious Adverse Event Reference
ChAdOx1-S (AZD1222) UK AstraZeneca, SK Bioscience, and Serum Institute of India Recombinant adenovirus vector 2–8 °C/6 months 2 Day 28–84 63%/≥18 Cerebral venous sinus thrombosis (CSVT) and other venous thrombosis with thrombocytopenia syndrome [2]
A clinical study in Sweden further reported no serious adverse events in the participants with the heterologous ChAdOx1-S/mRNA-1273 vaccination on day 7 to day 10 after the boost [26][36]. This was also found in the individuals with heterologous ChAdOx1-S/mRNA-1273 or ChAdOx1-S/BNT162b2 vaccination within seven days after the boost (n = 96). Regardless of interventions or intervals of heterologous ChAdOx1-S and mRNA vaccination, there were no serious adverse events regarding this heterologous vaccine regimen. However, the serious adverse events are still listed in the safety concerns of ChAdOx1-S and mRNA vaccine as very rare, which have been only observed in one per 100,000 to 250,000 ChAdOx1-S vaccinated people [33][43] and 2.5 to 24 per 10,000,000 mRNA vaccinated people [6][7][8][15,16,17]. Current studies in the safety of heterologous ChAdOx1-S and mRNA vaccination were based only on small populations. More clinical studies are needed to evaluate the safety of heterologous vaccination. The immunogenicity of heterologous ChAdOx1-S and mRNA vaccination is important for COVID-19 protection. Current studies have evaluated the immunogenicity of heterologous ChAdOx1-S and mRNA vaccination via detecting the level of SARS-CoV-2-specific IgG, the ability of neutralization antibody against wild type or variant SARS-CoV-2 or Spike-specific T-cell immune response (Table 2). These five studies reported the levels of SARS-CoV-2-specific IgG between homologous and heterologous vaccine groups [25][28][29][30][31][32][35,38,39,40,41,42]. Four of those studies independently showed that the level of SARS-CoV-2-Spike-specific IgG was significantly higher (in people who received ChAdOx1-S, then the boost of BNT162b2 or mRNA-1273) than that in people having homologous ChAdOx1-S/ChAdOx1-S vaccination regardless of the inoculating intervals [25][29][30][31][32][33][35,39,40,41,42,43]. Moreover, this IgG level of the heterologous vaccination groups was similar to or higher than that of the homologous vaccination with BNT162b2/BNT162b2 [28][29][32][38,39,42] or mRNA 1273/mRNA 1273 [31][41]. A similar observation was found on the level of SARS-CoV-2- receptor-binding domain-specific IgG [25][32][35,42]. One clinical study further showed that the heterologous ChAdOx1-S/BNT162b2 vaccination could induce a higher level of SARS-CoV-2-Spike-specific IgG in comparison to the heterologous BNT162b2/ChAdOx1-S vaccination [29][39].
Table 2. Studies of heterologous ChAdOx1-S with mRNA vaccination.
ReferenceCountryDesignInterval between DosesIntervention

(1st/2nd Dose)
Results
Johan N. et al., 2021 [25]SwedenAn open, multicenter phase IV study9–12 weeksHomologous 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
[3][4][5][11,12,13,14]
Ad26.COV2-S USA and Europe Janssen Pharmaceutical and Johnson & Johnson Recombinant adenovirus vector 2–8 °C/4.5 months

−20 °C/2 years
1 Day 0 66.9%/≥18 Cerebral venous sinus thrombosis (CSVT) and other venous vthrombosis with thrombocytopenia syndrome
Robert, H.S. et al., 2021 [23][24][26][3][4][5][6][12,13,14,15]
UKA single-blind, randomized, multicenter

phase II study
4 weeksHomologous 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
BNT162b2 USA and

Germany
Pfizer and BioNTech
Alberto, M.B. et al., 2021 [24][27]SpainAn open-label, randomized, controlled multicentermRNA

−70 °C/6 months 2 phase II study8–12 weeksWithout 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)
Day 21 92%/≥16 Anaphylaxis and myocarditis 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
[3][[8][125][7],14,16,17]
mRNA-1273 USA and

Europe
Moderna Biotech mRNA 2–8 °C/1 month
Tina S. et al., 2021 [31]

GermanyObservation study9–12 weeks:

ChAdOx1-S/ChAdOx1-S; ChAdOx1-S/BNT162b2 or mRNA-1273

3–6 weeks:

BNT162b2/BNT162b2 or mRNA-1273/mRNA-1273
−20 °C/6 months 2 Day 28 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
94.1%/≥18 Myocarditis, anaphylaxis, and other serious allergic reactions [3][5][8][9][10][12,14,17,18,19]
BBIBP-CorV (BIBP vaccine or Sinopharm COVID-19 vaccine) China Beijing Institute of Biological Products and Sinopharm Inactivated virus 2–8 °C/2 years 2 Day 14 78.1%/18–59 No adverse reports ** [3][5][12,14]
CoronaVac China Sinovac Inactivated virus 2–8 °C/2 years 2 Day 14 50.7%/18–59 51.1%/≥60 No adverse reports ** [3][5][11][12][12,14,20,21]
NVX-CoV2373 USA Novavax Recombinant protein 2–8 °C/not reported 2 Day 21 89.7%/≥18 * Myocarditis [13][22]
Gam-COVID-Vac (Sputnik V) Russia Gamaleya Research Institute of Epidemiology and Microbiology Heterologous recombinant adenovirus vector 2–8 °C for dry form or −18.5 °C for liquid form/not reported 1st dose rAd5; 2nd dose rAd6 Day 21 91.6%/≥18 No adverse reports ** [14][15][23,24]
* The vaccine efficacy was based on combination of vaccination with one or two dose. ** Accorded to WHO website.
 
Since the vaccination is voluntary, the rate of full immunization also depends on population acceptance [16][26]. Accompanied with the increased numbers of vaccinated people, more uncommon serious adverse events are found in the immunization with ChAdOx1-S, Ad26.COV2-S, BNT162b2, mRNA-1273, or NVX-CoV2373 (Table 1). As of the beginning of March 2021, the life-threatening cerebral or other venous sinus thrombosis related to homologous ChAdOx1-S vaccination (ChAdOx1-S/ChAdOx1-S) have frequently occurred, especially in young women [17][18][19][27,28,29]. Those uncommon serious adverse events may trigger the decline of COVID-19 vaccination, including those people who had received the first dose of ChAdOx1-S. These events have enhance the forming of vaccine hesitancy, which is a behavior of a delayed acceptance or refusal of vaccination despite the vaccination services which are available [16][20][26,30]. Subsequently, vaccine hesitancy may become one of the key factors to delay the completion of global herd immunity.
The status of vaccine shortage and vaccine hesitancy can affect the timing of global herd immunity. The use of heterologous vaccines may be beneficial for earlier reduction of the COVID-19 pandemic. Since the vaccine shortage and vaccine hesitancy slow the rate of herd immunity, the current vaccine regimen has been switched to heterologous vaccination from homologous vaccination [21][22][31,32]. Several studies have been reported for the safety and immunogenicity of heterologous ChAdOx1-S and mRNA vaccination (heterologous combing with first dose/second dose of ChAdOx1-S/mRNA and mRNA vaccine/ChAdOx1-S) [23][24][25][26][27][28][29][30][31][33,34,35,36,37,38,39,40,41]. However, the implication of heterologous ChAdOx1-S and mRNA vaccination against COVID-19 is still unclear. The safety and immunogenicity for each vaccine regmien are crtical factors to combat COVID-19. Hence, we conduct a systematic review to summarize the current findings on the safety and immuno-genicity of this heterologous vaccination and elucidate their implications against COVID-19.

2. Safety and Immunogenicity

The safety of heterologous ChAdOx1-S and mRNA vaccination was reported in five clinical studies [25][26][27][28][29][30][35,36,37,38,39,40] and one prospective study [32][42]. Two clinical studies had separately enrolled the participants for heterologous ChAdOx1-S/BNT162b2 vaccination from Spain (n = 451) [27][37] and Germany (n = 26) [28][38]. Two clinical studies utilized the same participants from the UK to separately evaluate the vaccine safety within seven and 28 days after the boost (n = 110) [24][29][34,39]. Another one was estimated the vaccine effectiveness (VE) of heterologous vaccine (ChAdOx1 with mRNA vaccine as the second dose) from Denmark [30][40]. The interval for heterologous vaccination of ChAdOx1-S/BNT162b2 was 8–12 weeks for the study in Spain [27][37], eight weeks for that in Germany [28][38], four weeks for that in the United Kingdom [25][29][35,39], and 82 days in Denmark [30][40]. For the prospective study, the individuals were screened who received the ChAdOx1-S/BNT162b2 with the 10–12-week vaccine interval (n = 104). Although the intervals were dissimilar, these studies all reported no serious adverse events regarding heterologous ChAdOx1-S/BNT162b2 vaccination after one [32][42], seven [26][27][36,37], 28 days [29][39], or more than one day [28][38]. The two clinical studies from the United Kingdom also enrolled the participants for heterologous BNT162b2/ChAdOx1-S vaccination with the four-week interval. All participants with heterologous BNT162b2/ChAdOx1-S vaccination did not present vaccine-related serious adverse events within seven [26][36] and 28 days [29][39] after boost (n = 114). The occurrence of serious adverse events was not related to the vaccination order of BNT162b2 and 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 [28]GermanyClinical study8 weeksHomologous 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 [29]UKA single blinded, randomized, multicenter, phase II, non-inferiority study4 weeksHomologous 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 [32]GermanyProspective study3 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. [30]DenmarkClinical study82 daysHeterologous 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.
Four studies reviewed as following, have shown the efficacy of neutralization antibody against wild type SARS-CoV-2 between homologous and heterologous vaccine groups [25][28][29][31][35,38,39,41]. The 50% of pseudovirus neutralization titer (PVNT50) in the heterologous ChAdOx1-S/BNT162b2 vaccinated people was significantly higher than that in the homologous ChAdOx1-S/ChAdOx1-S vaccinated people and was equal or similar to that in the homologous BNT162b2/BNT162b2 vaccinated people regardless of the inoculating intervals [28][29][38,39]. One clinical study showed that the percentage of inhibition of surrogate virus neutralization antibody in the groups of heterologous ChAdOx1-S/BNT162b2 or mRNA1273 vaccination was significantly higher than that in the homologous ChAdOx1-S/ChAdOx1-S vaccination [31][41]. Another study that utilized the real virus neutralization test found similar results between the groups of the heterologous ChAdOx1-S/mRNA1273 vaccination and the homologous ChAdOx1-S/ChAdOx1-S vaccination [25][35]. In addition, the efficacy of neutralization antibody against wild type SARS-CoV-2 in the heterologous ChAdOx1-S/BNT162b2 vaccination group was better than that of the heterologous BNT162b2/ChAdOx1-S vaccination group [29][39]. The efficacy of neutralization antibody against variant SARS-CoV-2 between homologous and heterologous vaccine groups which was detected in three studies [25][28][32][35,38,42]. The heterologous vaccination of ChAdOx1-S/BNT162b2 or ChAdOx1-S/mRNA-1273 produced a better neutralization capacity against alpha- or beta- SARS-CoV-2 when compared with that of the homologous vaccination of ChAdOx1-S/ChAdOx1-S or BNT162b2/BNT162b2 [25][28][32][35,38,42]. There were three studies which showed the Spike-specific T-cell immune response between the heterologous vaccine group and the homologous vaccine group [29][31][32][39,41,42]. This was detected by the production of IFN-γ or the level of IFN-γ+ T-cell in PBMC after Spike stimulation. The production of IFN-γ was significantly higher in the heterologous ChAdOx1-S/BNT162b2 vaccination than that in the homologous ChAdOx1-S/ChAdOx1-S [32][42]. Although the level of IFN-γ+ T-cell in PBMC was not significantly higher in the heterologous ChAdOx1-S/BNT162b2 group [29][39], the other study showed that the level of antigen-specific T-cells (CD69+ IFN-γ+ CD8+ T-cell) was significantly higher in the heterologous ChAdOx1-S/BNT162b2 or mRNA-1273 group [33][43]. Overall, the heterologous ChAdOx1-S and mRNA vaccination could induce a robust immune response against COVID-19 in comparison with the homologous ChAdOx1-S/ChAdOx1-S.