To mix or not to mix? A rapid systematic review of heterologous prime–boost covid-19 vaccination

ABSTRACT

Introduction

Coronavirus disease 2019 (COVID-19) has had an enormous impact worldwide, and vaccination is believed to be the method that will control the pandemic. Several types of vaccines developed using different platforms have been authorized, but the immunogenicity and reactogenicity of heterologous prime–boost vaccination with different vaccines remain largely unclear.

Areas covered

Electronic databases including PubMed, Embase, medRxiv, Research Square, and SSRN were searched to investigate the immunogenicity and reactogenicity associated with heterologous vaccination.

As of 30 June 2021, four trials including 1,862 participants were identified. Heterologous administration of BNT162b2 (BNT) in ChAdOx1 (ChAd)-primed participants (ChAd/BNT) showed noninferior immunogenicity to homologous BNT administration (both prime and booster were BNT vaccines, BNT/BNT) with tolerable reactogenicity and higher T cell responses. Compared with homologous ChAdOX1 vaccination (ChAd/ChAd), heterologous ChAd/BNT was found to elicit higher immunogenicity (ChAd/BNT vs. ChAd/ChAd, antibody titer ratio: 9.2).

Expert opinion

Our systematic review found robust immunogenicity and tolerable reactogenicity of heterologous administration of a BNT162b2 boost in ChAdOx1-primed participants. An additional benefit of stronger T cellular immunity was also observed. Heterologous vaccination is a reasonable and feasible strategy to combat COVID-19. Further studies are warranted to confirm the benefits and identify the optimal combinations, doses, and intervals.

KEYWORDS:

• COVID-19
• Sars-COV-2
• vaccination
• heterologous
• boost
• BNT162B2
• chadox1
• mRNA

Article highlights

• COVID-19 vaccines produced using different platforms have been widely administered, but challenges have arisen, including vaccine supply shortages, perceived serious but very rare adverse events after the first dose, the much-publicized thromboembolic effects, and the emergence of variants of concern. Heterologous prime–boost vaccination refers to a scheme in which the booster vaccination and prime vaccination utilize different platforms; heterologous vaccination might be an alternative strategy, but the immunogenicity and reactogenicity remain largely unclear.

• Our systematic review identified four trials with 1862 participants, and we found robust immunogenicity of heterologous administration of BNT162b2 (BNT) in ChAdOx1(ChAd)-primed participants (ChAd/BNT).

• Homologous BNT162b2 vaccinations and heterologous ChAd/BNT had the highest antibody titers.

• Heterologous ChAd/BNT had the highest T cellular responses.

• Higher neutralizing activities against variants of concern B.1.1.7, B.1.351, and B.1.617 were observed in heterologous ChAd/BNT vaccinations.

• Although adverse events were more commonly reported in the BNT-boosted participants, reactogenicity was tolerable in all combinations.

• Heterologous vaccination was a feasible and reasonable strategy. Further studies are encouraged to confirm the clinical effectiveness and identify the optimal combinations, doses, and intervals.

Acknowledgments

We thank everyone’s efforts to combat COVID-19.

Declaration of interest

The authors declare no conflict of interest.

Reviewer disclosures

A reviewer has declared they are an employee of EpiVax, Inc., a biotech company that is developing a COVID-19 vaccine. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Authors’ contributions

NCC, HC, and CYL involved in conceptualization; YKT, YNH, YLT, SLW, LC, DTNH, FYH, and CYL performed literature search and screen. YNH, YLT, and CYL performed quality assessment and analysis; YKT and CYL were responsible for methodology and software; NCC wrote the first draft. All authors have read and agreed to the published version of the manuscript.

Ethical Approval and Consent to participate

This study was approved by the Institutional Review Board of the MacKay Memorial Hospital, Taipei, Taiwan (approval number, 20MMHIS140e).

Availability of supporting data

The datasets used for the analysis in the present study are available from the corresponding author on reasonable request.

Additional information

Funding

This research received no external funding.