key: cord-0749598-0kk0hcu7
authors: Lv, Jingjing; Wu, Hui; Xu, Junjie; Liu, Jiaye
title: Immunogenicity and safety of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine: a systematic review
date: 2022-05-13
journal: Infect Dis Poverty
DOI: 10.1186/s40249-022-00977-x
sha: 5eb9862e3031ffc5d26da2089adff15786cf8603
doc_id: 749598
cord_uid: 0kk0hcu7

BACKGROUND: Heterologous prime-boost with ChAdOx1 nCoV-19 vector vaccine (ChAd) and a messenger RNA vaccine (BNT or mRNA-1273) has been widely facilitating mass coronavirus disease 2019 (COVID-19) immunisation. This review aimed to synthesize immunogenicity and reactogenicity of heterologous immunisations with ChAd and BNT (mRNA-1273) vaccine compared with homologous ChAd or BNT (mRNA-1273) immunisation. METHODS: PubMed, Web of Science, and Embase databases were searched from inception to March 7, 2022. Immunogenicity involving serum antibodies against different SAS-CoV-2 fragments, neutralizing antibody, or spike-specific T cells response were compared. Any, local and systemic reactions were pooled by meta-analysis for comparison. RESULTS: Of 14,571 records identified, 13 studies (3024 participants) were included for analysis. Compared with homologous BNT/BNT vaccination, heterologous ChAd/BNT schedule probably induced noninferior anti-spike protein while higher neutralizing antibody and better T cells response. Heterologous ChAd/BNT (mRNA-1273) immunisation induced superior anti-spike protein and higher neutralizing antibody and better T cells response compared with homologous ChAd/ChAd vaccination. Heterologous ChAd/BNT (mRNA-1273) had similar risk of any reaction (RR = 1.30, 95% CI: 0.86−1.96) while higher risk of local reactions (RR = 1.65, 95% CI: 1.27−2.15) and systemic reactions (RR = 1.49, 95% CI: 1.17−1.90) compared with homologous ChAd/ChAd vaccination. There was a higher risk of local reactions (RR = 1.16, 95% CI: 1.03−1.31) in heterologous ChAd/BNT (mRNA-1273) vaccination compare with homologous BNT/BNT but a similar risk of any reaction (RR = 1.03, 95% CI: 0.79−1.34) and systemic reactions (RR = 0.89, 95% CI: 0.60−1.30). CONCLUSIONS: Heterologous ChAd/BNT schedule induced at least comparable immunogenicity compared with homologous BNT/BNT and better immunogenicity compared with homologous ChAd/ChAd vaccination. The synthetical evidence supported the general application of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40249-022-00977-x.

higher rates of coronavirus disease 2019 (COVID-19)-induced complications and mortality than the general population [2] [3] [4] . Frequently emerging vital mutations have raised significant concerns globally. Active immunization is the most efficient and vital strategy for fighting against this emerging infectious disease. Several vaccines with proven effectiveness are being deployed globally, including Pfizer-BioNTech's mRNA COVID-19 vaccine (BNT) [5] , Oxford-AstraZeneca's adenovirus vectored vaccine (ChAd) [6] , China's Sinovac [7] , and Sinopharm vaccines [8] . Mass vaccination raised hope for expeditious ending the COVID-19 pandemic.

BNT and ChAd have been the most widely used authorized COVID-19 vaccines worldwide. Due to a potentially higher risk of thromboembolic events in younger individuals [9] , several European countries restricted their recommendations for ChAd COVID-19 vaccination to older individuals (e.g., older than 55 years in France and older than 60 years in Germany) [10, 11] . Heterologous boost immunisation with an mRNA vaccine was consequently recommended for younger individuals who had already received the first immunization with the ChAd COVID-19 vaccine. The changed recommendations contributed to several real-world studies to compare the immunogenicity and reactogenicity of heterologous ChAd/mRNA immunisation with homologous platform vaccines [12, 13] . Additionally, a randomised, controlled trial provided robust evidence on the safety and immunogenicity of heterologous versus homologous prime-boost schedules [14] . Although a majority of previous studies concluded that heterologous schedules incorporating vector vaccines and mRNA vaccines could induce comparable or superior humoral and cellular responses compared with homologous immunisation, the world health organization has not recommended heterologous prime-boost COVID-19 vaccination as an alternative strategy in the necessary settings. So far, there has been scarce pooled evidence on the safety and immunogenicity of heterologous COVID-19 vaccination, which is urgently needed for updating vaccination guidance worldwide.

Except for sufficing changes in guidance for vaccine usage, heterologous COVID-19 vaccination could also address shortages of vaccines to avoid delayed administration of the second dose and provide an alternative strategy for individuals who develop a contraindication to a specific vaccine after their first dose. Moreover, the emerging SARS-CoV-2 variants of concern have drawn attention, and breakthrough infections have been reported. Heterologous vaccination might induce an enhanced or more durable humoral or cellular immune response to combat COVID-19 variants [15] . In addition, it has been proven that the patients with cancer would have reduced or short-term COVID-19 vaccine efficacy [16, 17] . Heterologous vaccination might be an alternative strategy for improving immunogenicity in this particular population.

Therefore, we conducted this systematic review to pool the evidence on the immunogenicity and safety of heterologous versus homologous prime-boost vaccination schedule.

Relevant studies were searched in PubMed, Embase, and Web of Science from their inception to March 7, 2022 using a combination of comprehensive keywords, such as 'COVID-19, ' 'coronavirus disease 2019, ' 'severe acute respiratory syndrome coronavirus 2, ' 'SARS-CoV-2, ' 'vaccination, ' and 'vaccine' with Boolean operators and MeSH terms. No constraints were placed on language. Besides, we searched relevant systematic reviews for additional papers. The process of searching, reviewing, selecting literature was independently performed by two authors. Discrepancies were resolved through consultation with a third author.

Published papers were eligible for inclusion if they met the inclusion criteria: (1) studies were observational studies (prospective or retrospective cohort) or randomized trials with a minimum of ten adult participants in any subject group, (2) studies at least involved one type of heterologous prime-boost COVID-19 vaccination (i.e., mRNA vaccine boosting after ChAd vaccine priming, ChAd vaccine boosting after mRNA vaccine priming), (3) studies at least had one type of homologous primeboost COVID-19 vaccination as the control group (i.e., mRNA vaccine boosting after mRNA vaccine priming, ChAd vaccine boosting after ChAd vaccine priming), (4) studies reported at least one of the outcomes of interest after boosting vaccination: serum antibodies against different SAS-CoV-2 fragments, and neutralizing antibody.

The exclusion criteria were as follows: (1) studies involved subjects who were ever or currently infected with SARS-CoV-2, (2) studies involved subjects with impaired immunity or immunosuppression, (3) studies involved subjects with severe diseases, such as patients who needed haemodialysis, (4) studies without baseline data reported, (5) studies were reviews.

We extracted the data according to a standardized form: study characteristics (first author, year of publication, country of origin, and study design), subject characteristics (sample size, age, gender), vaccination strategies (priming vaccine, interval time between priming and boosting vaccination, boosting vaccine), and outcomes (interval time between boosting vaccination and outcomes evaluation, levels of serum antibodies against different SAS-CoV-2 fragments and neutralizing antibody, frequencies and phenotype of specific T cells and B cells, cytokine levels, and the number of adverse events). This process was also conducted by two authors independently and checked by a third author.

We used the Newcastle-Ottawa Scale quality assessment scale for the quality assessment of cohort studies [18] , which is comprised of three domains: selection, comparability, and outcome. The total score of the three domains is nine, with a score of 7−9 high quality (low risk of bias), 4−6 fair quality (moderate risk of bias), and 1−3 low quality (high risk of bias), respectively. In addition to cohort studies, we also included randomized controlled trials (RCTs) in this systematic review. The risk of bias in RCTs was assessed using version 2 of the Cochrane riskof-bias tool for randomized trials [19] .

Primary outcomes were immunogenicity of heterologous and homologous COVID-19 vaccination, including anti-S1 IgG, anti-RBD IgG, anti-full spike IgG, ACE2-RBD binding inhibition (%), reciprocal titres of neutralizing antibodies, neutralization capacities, and neutralization inhibition (%) after boosting vaccination. The second outcomes included frequency and phenotype of spikespecific B cells and T cells, IFN γ-secreting T cells specific to spike protein epitopes, and local and systemic reactions after boosting vaccination.

We tabulated the extracted information using Microsoft Excel version 2016 (Microsoft Office, CA, USA) spreadsheets and performed a meta-analytical evaluation using R 4.0.3. The techniques used to measure SARS-CoV-2 specific antibodies and criteria for positivity varied in different studies. Thus, meta-analysis was inappropriate to compare the immunogenicity of different studies. Instead, a qualitative description was mainly used to compare and pool the immunogenicity. Concerning adverse events (AEs) analysis, risk ratio (RR) and 95% confidence intervals (CIs) were used as the comparative index under evaluation. RR is estimated as the event rate in the trial group divided by the same rate in the control group. A random-effects, Mantel-Hanzeal model (95% CI) was used to determine effect sizes between studies. Statistical heterogeneity was assessed using the Cochrane Q test and I 2 statistics. The assessment of potential publication bias by funnel plots and Egger's test were expected; however, it was not done. The reason is that there were fewer than ten studies included in forest plot analysis. In this case, it is not recommended the funnel plots and Egger's test because it could yield misleading results [20] .

As of March 7, 2022, the literature search initially identified 14,571 articles. We then selected articles according to the defined inclusion and exclusion criteria. Figure 1 depicts the process of study selection and reasons for exclusions. A total of 4212 duplicate articles in different databases were removed. We screened the title and abstract of the remaining articles and excluded ineligible articles. Finally, 52 full-text articles were further assessed for eligibility. Twenty-two studies were not included in our review because they don't use the heterologous prime-boost vaccination. Five studies without mRNA or adenoviral vectored COVID-19 vaccine, six studies without homologous prime-boost COVID-19 vaccination as control groups, one study without immunogenicity, one with a sample size less than ten, one with a pre-existing clinical disease, one review, one case report, and one animal study were excluded, respectively.

Finally, 13 studies [12] [13] [14] [15] [21] [22] [23] [24] [25] [26] [27] [28] [29] from 52 articles were identified that fulfilled our inclusion and exclusion criteria, Nine studies were conducted in Germany [12, 13, 15, 21-24, 26, 27] two in UK [14, 29] , and two in France [25, 28] . Of these studies, 12 were observational studies [12, 13, 15, [21] [22] [23] [24] [25] [26] [27] [28] [29] and one was randomized trial [14] . All studies involved ChAd/BNT (mRNA-1273) schedule and two study involved BNT/ChAd schedule [14, 24] . The characteristics of the included studies are summarized in Table 1 .

The quality assessment scores for included cohorts are shown in Additional file 1: Table S1 . Overall, four high-quality cohort studies [22, 25, 28, 29] and eight fairquality cohort studies [12, 13, 15, 21, 23, 26, 27, 30] were included in this systematic review. The randomized trial [14] was considered to have a low risk of bias.

In this systematic review, prime-boost vaccination schedules include ChAd/BNT (mRNA-1273) and BNT/ChAd. All studies involved ChAd/BNT (mRNA-1273) heterologous schedule and had BNT/BNT (mRNA-1273) as the control group, and meanwhile, ten of which also had ChAd/ChAd as the control group [12-15, 21, 23, 24, 26, 27, 29] .

Thirteen studies [12] [13] [14] [15] [21] [22] [23] [24] [25] [26] [27] [28] [29] involved 14 times of comparisons between ChAd/BNT(mRNA-1273) heterologous schedule and homologous BNT/BNT (mRNA-1273/mRNA-1273), four of them studies reported comparative efficacy on anti-RBD IgG and all of them did not find significant difference on this outcome [13, 21, 25, 26] . Eight studies [12-14, 21, 22, 25, 28, 29] reported comparative effectiveness on anti-S protein IgG, seven of them [12-14, 21, 25, 28, 29] showed comparable efficacy on this indicator, and one of them [22] found that ChAd/BNT induced higher cumulative anti-spike-IgM and IgG concentrations. Ten studies [13] [14] [15] [21] [22] [23] [24] [25] [26] [27] supplied 11 times of comparison on neutralizing antibody, six of them [13, 15, 22, [25] [26] [27] with seven times of comparison found that ChAd/BNT(mRNA-1273) heterologous schedule could induce better response on neutralizing antibody involving against B.1.351 variant and B.1.1.7 variant, two of them [14, 21] found similar response, and two of them [23, 24] found a lower reciprocal titres of neutralizing antibody against Delta variant. Four studies [13, 15, 25, 26] explored spike-specific IFN-γ secretion, three of them [13, 15, 26] discovered that heterologous ChAd/BNT(mRNA-1273) immunisation could induce higher spike-specific IFN-γ secretion, and one of them found similar whole-blood IFN-γ [25] (Table 2 ). In conclusion, it seemed that the majority of studies indicated heterologous ChAd/BNT(mRNA-1273) immunisation schedule induced superior or at least comparable humoral and cellular response against SARS-CoV-2 compared with homologous BNT/BNT immunisation schedule, while definite conclusion has yet been reached on the response against variants.

Of the ten studies [12-15, 21, 23, 24, 26, 27, 29] involved ChAd/BNT (mRNA-1273) heterologous schedule with homologous ChAd/ChAd as a control group, two studies [13, 26] reported comparative efficacy on anti-RBD IgG, one of which showed similar and another showed higher RBD IgG in ChAd/BNT(mRNA-1273) groups compared Studies in the table were arranged by the types of prime-boost immunization strategies. Some studies may include more than one type of prime-boost immunization strategy or more than one comparative group, so these studies were presented in more than one row b All the comparisons in the table indicate the value of heterologous prime-boost vaccination vs that of homologous prime-boost vaccination with that in homologous ChAd/ChAd groups. Six studies [12, 14, 15, 21, 26, 29] reported comparative efficacy on anti-S protein IgG, all of which showed a higher anti-S IgG level in ChAd/BNT (mRNA-1273) groups compared with that in homologous ChAd/ChAd groups. Nine studies [12-15, 21, 23, 24, 26, 27] reported comparative efficacy on neutralizing antibody and found better responses in ChAd/BNT (mRNA-1273) groups compared with homologous ChAd/ChAd groups; especially, two study [15, 24] 

Two studies [14, 29] investigated the difference of specific immune response between heterologous BNT/ChAd and homologous BNT/BNT vaccination, one of which found that heterologous BNT/ChAd induced inferior anti-S IgG and neutralizing antibody while similar T cell response compared with homologous BNT/BNT vaccination, the other found similar response in anti-S rotein IgG. Meanwhile, the two studies also compared the immune response between heterologous BNT/ChAd and homologous ChAd/ChAd vaccination, both of which found heterologous BNT/ChAd schedule induced higher anti-S IgG and one study also found heterologous BNT/ChAd schedule induced higher neutralizing antibody compared with homologous ChAd/ChAd schedule ( Table 2) .

Four studies [13, 14, 21, 26] compared AEs incidences between heterologous ChAd/BNT (mRNA-1273) and homologous BNT/BNT or ChAd/ChAd vaccination. All of them used standardized questionnaires to collected AEs after vaccination (Additional file 1: Table S2 ). We conducted a meta-analysis to compare the frequen- Fig. 2B ). One study reported the frequencies of severe adverse events (SAE) were 9.5% in ChAd/ChAd, 11.3% in ChAd/BNT, 1.2% in BNT/BNT, and 7.8% in BNT/ChAd, respectively [14] . Another study reported the frequencies of severe local adverse events were 4% in BNT/BNT, 3% in ChAd/ChAd, and 7% in ChAd/BNT, respectively; the frequencies of severe systemic adverse events were 6% in BNT/BNT, 6% in ChAd/ChAd, and 2% in ChAd/BNT, respectively [13] . However, statistic tests were not conducted in the frequencies of SAE between heterologous and homologous vaccination in the two studies. Based on these crude data, the frequencies of SAE seemed to be comparable between heterologous and homologous vaccination.

The P value for Cochrane's Q test suggested high heterogeneity across studies for ChAd/BNT (mRNA-1273) vs BNT/BNT strategy in the assessment of any events and systematic and studies for ChAd/BNT (mRNA-1273) vs ChAd/ChAd strategy in any events assessment (P < 0.01, Fig. 2 ). Potential publication bias was not assessed because the number of studies was small (< 10) in all of the above meta-analyses.

Equitable access to safe and effective vaccines is critical to ending the COVID-19 pandemic. In the situation of vaccines shortage and observed higher risk of severe adverse events for some subgroups after vaccination, optimizing the vaccination based on available COVID-19 vaccines is urgently needed. Our systematic review showed robust immunogenicity of heterologous primeboost immunisation with ChAd and BNT. Compared with homologous BNT/BNT vaccination, heterologous ChAd/BNT (mRNA-1273) schedule probably induced non-inferior anti-spike protein while higher neutralizing antibody and better T cells response. Heterologous ChAd/BNT (mRNA-1273) immunisation induced superior anti-spike protein and higher neutralizing antibody and better T cells response compared with homologous ChAd/ChAd vaccination. Reactogenicity was tolerable in heterologous ChAd/BNT compared with homologous ChAd/ChAd or BNT/BNT vaccination. In addition, heterologous BNT/ChAd vaccination schedule showed weaker immunogenicity than homologous BNT/BNT vaccination. The robust immunogenicity elicited by heterologous ChAd/BNT vaccination schedule provides evidence for the feasibility of this promising vaccination strategy. Antibodies to S protein, virus neutralization tests (VNT), pseudovirus neutralization tests (pVNT), and competitive neutralization tests (cVNT) of SARS-CoV-2 have been the most common antibody testing for evaluating the immune response of COVID-19 vaccination. The detecting methods of SARS-CoV-2 anti-spike (RBD or S) IgG and neutralizing antibodies were various in the included articles (Additional file 1: Table S3 ), which made the quantitative analysis of immunogenicity by meta-analysis unavailable. A significant number of studies have established associations between humoral responses and vaccine efficacy, such as against symptomatic diseases, severe diseases, and hospitalisation [31, 32] . Based on the above indicators, this systematic review found that heterologous ChAd/BNT vaccination induced humoral responses at least as high as or even better than those induced after homologous ChAd/ChAd or BNT/ BNT schedule. The mechanisms of immune response induced by heterologous prime-boost vaccination are incompletely understood. Several factors, including the selection of antigen, type of vector, adjuvant, the order of vector injection, and the intervals between different vaccinations, influence the responses of prime-boost immunization [33] . Although neutralization against P.1, B.1.1.7, and B.1.351 induced both by ChAd and BNT were reduced, the protective efficacy against symptomatic COVID-19 caused by variants differed between homologous ChAd/ChAd and BNT/BNT schedule. [34] [35] [36] Thus, heterologous ChAd/BNT vaccination was expected to induce more robust immune responses against novel viral variants. Indeed, two studies in this review confirmed heterologous ChAd/BNT vaccination induced higher titres of neutralizing antibodies against P.1, B.1.1.7, and B.1.351 variants [12, 15] . In the setting of vaccine shortage and rapid expanding variants, heterologous ChAd/BNT vaccination might be a promising vaccination schedule against COVID-19 pandemic, beyond passive substitution vaccination due to rare severe adverse events.

The quantity and function of T-cell responses play a crucial part in the prognostication of COVID-19 and monitoring immune responses to SARS-CoV-2 vaccination and population-based immunity to SARS-CoV-2 variants of interest [37] . One study evaluated the immune response of homologous and heterologous mRNA and vector-based COVID-19 vaccine schedules in solid organ transplant recipients. It showed that cellular immunity was more frequently found (64.7%) than humoral response (35%), which indicated that assessment of antibodies was insufficient to identify COVID-19-vaccine responders [38] . Among ten included studies in this systematic review, five studies [12] [13] [14] [15] 26] compared the spike-specific CD4 or CD8 T cell response and all these studies found that heterologous ChAd/BNT vaccination induced better spike-specific T cell response. Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Increased interferon-gamma (IFN-γ) levels early after boost correlated with spike antibody levels, implying IFN-γ as a valuable biomarker of effective humoral immunity development in response to vaccination [39] . Specially, four studies [12, 13, 15, 26] in this systematic review showed a higher IFN-γ secretion in heterologous ChAd/BNT vaccination groups. Together with robust humoral and cellular responses, this review concluded heterologous ChAd/BNT vaccination could induce a broader immune response.

Because of rare but evidenced severe adverse events after vaccination with ChAd COVID-19 vaccine, heterologous ChAd/BNT vaccination has become the most common heterologous schedule. Nevertheless, heterologous vaccination with the reverse sequential schedule or other platforms might be needed in real-world immunization practice. One study included in this review showed that heterologous BNT/ChAd vaccination induced inferior anti-S IgG and neutralizing antibody compared with homologous BNT/BNT schedule while superior responses compared with homologous ChAd/ ChAd vaccination [14, 40] . This result implied that heterologous BNT/ChAd is not an optimal sequential vaccination schedule taking no account of supply shortages and contraindications to prime vaccine. Further studies are needed to explore the immune response of various heterologous prime-boost immunization.

Decreases over time of vaccine-induced neutralising antibodies against SARS-CoV-2 have been observed with several COVID-19 vaccines [40, 41] . Moreover, many countries are experiencing a resurgence of COVID-19 mainly due to variants of SARS-CoV-2. In response, considering the administration of the third dose of COVID-19 vaccine as a booster dose has been the research interest for addressing potential waning immunity over time and reduced effectiveness against the delta variant. One study found that heterologous two BBIBP/ BNT could induce higher anti-S IgG titre compared with the homologous schedule in BNT/BNT vaccination [30] . Consistent with this study, a third dose of the BNT COVID-19 vaccine after homologous BNT/BNT in Israel [42] , a third dose of CoronaVac after homologous Coro-naVac/CoronaVac in China [43] , and seven COVID-19 vaccines as a third dose (booster) following two doses of ChAd COVID-19 or BNT in the UK [44] all resulted in a remarkable increase in the concentration of antibodies or increase in effectiveness for preventing severe COVID-19 outcomes. These results implied that a heterologous third dose after homologous prime-boost vaccination could be an alternative immuniz ation schedule. A longer prime-boost interval is reported to induce a higher post-boost SARS-CoV-2 anti-spike IgG both for ChAd/ChAd [43] and for BNT/BNT [45] . Of the ten studies [12-15, 21, 23, 24, 26, 27, 29] involved ChAd/ BNT (mRNA-1273) heterologous schedule with homologous ChAd/ChAd as a control group, the prime-boost intervals were similar between the two schedules. Thus, the difference on the immunogenicity probably attributed to the vaccination schedules. However, of the 13 studies [12] [13] [14] [15] [21] [22] [23] [24] [25] [26] [27] [28] [29] involved ChAd/BNT (mRNA-1273) heterologous schedule with homologous BNT/BNT (mRNA-1273/mRNA-1273) as a control group, only two studies [14, 29] had comparable prime-boost intervals between the two schedules. Both the two studies showed the comparable immunogenicity between heterologous and homologous vaccination. However, for majority of included studies involved comparison between ChAd/ BNT (mRNA-1273) and BNT/BNT (mRNA-1273/ mRNA-1273), both prime-boost interval and vaccination schedule became the main confounders in the analysis of immunogenicity after boost vaccination. In addition, age, sex, race, and individual immune status also affected the comparison of immunogenicity between the heterologous and homologous vaccination. Moreover, there has not been studies directly comparing immunogenicity between different prime-boost intervals in single heterologous arm. Thus, whether prime-boost interval affects immunogenicity awaits future studies.

One of the most important purposes of heterologous ChAd/BNT vaccination was to address the high risk of thromboembolic events for patients who would receive homologous ChAd/ChAd vaccination. As expected, none of the thromboembolic events and other vaccination related severe events were observed in heterologous ChAd/BNT vaccination groups from included studies. Our systematic review found that heterologous primeboost vaccination leads to a slightly higher risk of local reactions and systemic reactions compared with homologous ChAd/ChAd vaccination and a higher risk of local reactions compared with homologous BNT/BNT, which mainly resulted from the study of Tina Schmidt, et al. conducted in Germany [26] . This study showed that the reactions after the second dose were mainly determined by the severity of the priming vector vaccines. Despite that, heterologous boosting was well tolerated and comparable to homologous mRNA boosting. In addition, study design, study population demographics, and collection methods of adverse events could lead to differences in the assessment of this outcome.

This systemati c review provided a higher level of evidence on the immunogenicity and safety in heterologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine. This promising schedule provide an alternative strategy not only for relieving the shortage of vaccines but also for combating various variants during the global pandemic. Nevertheless, several issues are needed to be addressed in future. Firstly, our systematic review only included two kinds of COVID-19 vaccine with different technical routes. More studies especially high qualitied randomized controlled trials on heterologous and homologous schedules with other technical routes, e.g. inactivated, protein subunit could be conducted for providing more flexibility for future vaccination strategies. Furthermore, direct comparisons of immunogenicity and safety between different heterologous prime-boost schedules are also necessary. Secondly, the influence of prime-boost interval, race, and other potential confounders on immunogenicity should be evaluated for identifying the independent role of heterologous vaccination. Thirdly, some particular population subgroups (e.g. immunocompromised individuals, cancer patients, haemodialysis patients, etc.) have weaker immunogenicity compared with that in general population. Thus, a strengthening strategy is essential for these particular population. Whether heterologous vaccination could elicit robust immune responses in these particular population has not been determined yet. Fourthly, clinical outcomes including the infection rate, COVID-19 hospitalization, the occurrence of severe cases, and mortality were vital of future researches in heterologous vaccination. Lastly, waning of immune responses has been observed after COVID-19 vaccination, with reduced protection against infection and some loss of protection against hospitalization and death. Thus, comparison between heterologous and homologous COVID-19 booster vaccination in individuals who have completed full course of vaccination is encouraged.

Our systematic review is not without limitations. First, we didn't make the meta-analyses and pooled evidence for immunogenicity of different studies due to inconsistency of various evaluation indicators and measurement methods in limited included studies. Despite this, we tried to obtain deterministic conclusions by qualitative synthesis analyses. Second, the number of studies and sample size of subjects available in some evaluated strategies was small. The language restriction to English may narrow the breadth of our search. Third, there were no more available data to assess other heterologous combination styles, such as CoronaVac, ZF2001, etc. Fourth, the efficacy of different heterologous schedules for individuals with underlying medical conditions in this metaanalysis was not considered. Thus, the conclusion should be extrapolated carefully in individuals with underlying medical conditions. Further studies are necessary to explore optimal heterologous schedules applicable to those individuals. Fifthly, the comparison on efficacy of different heterologous schedules would provide more valuable information for public health policy decisionmaking. However, few studies directly compared the efficacy of different heterologous schedules. The inconsistent testing methods of immune response in the included studies limited the indirect comparison. Lastly, all included studies in this review had not reported the clinical efficacies including infection rate, hospitalization rate, and mortality after vaccination. These efficacies should be the crucial evaluation indicators in future.

Our review showed that heterologous ChAd/BNT schedule induced at least comparable immunogenicity compared with homologous BNT/BNT and better immunogenicity than homologous ChAd/ChAd vaccination. Despite more common adverse in heterologous ChAd/BNT immunisation, they were tolerant, and no serious adverse events were observed. Heterologous ChAd/BNT vaccination is an evidence-based promising vaccination schedule for combating the COVID-19 pandemic.

The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s40249-022-00977-x.

Additional file 1: Table S1 . Assessment of quality of the included observational studies (Newcastle-Ottawa Quality Assessment Scale). Table S2 . Collection methods of adverse events and the frequencies of specific adverse events in the included studies. Table S3 . Testing methods of anti-SARS-CoV-2 IgG, Neutralizing Antibodies, and cellular immunity in the included studies

Novel Coronavirus (2019-nCoV) situation reports

COVID-19 in cancer and non-cancer patients

COVID-19 in cancer patients may be presented by atypical symptoms and higher mortality rate, a case-controlled study from Iran

Multicenter study of antibody seroprevalence against COVID-19 in patients presenting to iranian cancer centers after one year of the COVID-19 pandemic

Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebocontrolled, phase 3 trial in Turkey

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial

Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination

Covid-19: quelle stratégie vaccinale pour les moins de 55 ans ayant déjà reçu une dose d' AstraZeneca?

Aktualisierung der COVID-19-Impfempfehlung und die dazugehörige wissenschaftliche Begründung

Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination

Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study

Safety and immunogenicity of heterologous versus homologous primeboost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

mRNA vaccines enhance neutralizing Immunity against SARS-CoV-2 variants in convalescent and ChAdOx1-primed subjects

COVID-19 vaccination and cancer, the need for more data

Immunogenicity and safety of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV) in patients with malignancy

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

er_ 10/ 10_4_ 3_1_ recom menda tions_ on_ testi ng_ for_ funnel_ plot_ asymm etry

Cochrane Handbook for Systematic Reviews of Interventions Version

Heterologous ChAdOx1 nCoV-19/BNT162b2 prime-boost vaccination induces strong humoral responses among health care workers. Vaccines (Basel)

Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell reactivity against prevalent SARS-CoV-2 variants

Robust induction of neutralizing antibodies against the SARS-CoV-2 Delta variant after homologous Spikevax or heterologous Vaxzevria-Spikevax vaccination

Neutralization of the SARS-CoV-2 Delta variant after heterologous and homologous BNT162b2 or ChAdOx1 nCoV-19 vaccination

Immunogenicity and efficacy of heterologous ChAdOx1-BNT162b2 vaccination

Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination

Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2

An immunogenicity report for the comparison between heterologous and homologous prime-boost schedules with ChAdOx1-S and BNT162b2 vaccines

Real-world data on immune responses following heterologous prime-boost COVID-19 vaccination schedule with Pfizer and AstraZeneca vaccines in England

Immunogenicity and reactogenicity of BNT162b2 booster in BBIBP-CorVvaccinated individuals compared with homologous BNT162b2 vaccination: results of a pilot prospective cohort study from Lebanon

Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data

Comparative effectiveness of Moderna

Prime-boost vaccine strategy against viral infections: mechanisms and benefits

Effectiveness of ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection during the delta (B.1.617.2) variant surge in India: a test-negative, case-control study and a mechanistic study of post-vaccination immune responses

Effectiveness of mRNA-1273 against delta, mu, and other emerging variants of SARS-CoV-2: test negative case-control study

National Study Group for C-V. Effectiveness of the BNT162b2 COVID-19 vaccine against the B.1.1.7 and B.1.351 variants

The potential clinical utility of measuring severe acute respiratory syndrome coronavirus 2-specific T-cell responses

Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients

Systemic IL-15, IFN-gamma, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients

Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for COVID-19

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year submit your research ?

Immunogenicity and safety of a third dose of CoronaVac, and immune persistence of a twodose schedule, in healthy adults: interim results from two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

Extended interval BNT162b2 vaccination enhances peak antibody generation

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. 1 

JL conceived and supervised the study; JL, JLv, HW designed the study; JLv, HW, JX designed the study search terms and identified studies for inclusion; JL, JLv, HW designed data extraction template; JLv, HW, JL conducted data extraction; HW, JX assessed data quality; JL, JLv, JX analysed and/or interpreted data; JLv, HW drafted the manuscript; All authors critically reviewed or revised the manuscript and approved the final version of the manuscript.

Not applicable.

All data generated or analysed during this study are included in this published article and its Additional files.

Ethic approval and consent to participate Not applicable.

Not required.

Jingjing Lv, Hu Wu, Junjie Xu, and Jiaye Liu declare that they have no conflict of interest.