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Review 1: "Distinct Immune Signatures Discriminate SARS-CoV-2 Vaccine Combinations"

Published onOct 29, 2022
Review 1: "Distinct Immune Signatures Discriminate SARS-CoV-2 Vaccine Combinations"
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key-enterThis Pub is a Review of
Distinct immune signatures discriminate SARS-CoV-2 vaccine combinations

AbstractSeveral vaccines have been found effective against COVID-19, usually administered in homologous regimens, with the same vaccine used for the prime and boost doses. However, recent studies have demonstrated improved protection via heterologous mix-and-match COVID-19 vaccine combinations, and a direct comparison among these regimens is needed to identify the best employment strategies. Here, we show a single-cohort comparison of changes to the humoral and cellular immune compartments following five different COVID-19 vaccines spanning three technologies (adenoviral, mRNA and inactivated vaccines). These vaccines were administered in a combinatorial fashion, resulting in sixteen different homologous and heterologous regimens. SARS-CoV-2-targeting antibody titres were highest when the boost dose consisted of mRNA-1273, independent of the vaccine used for priming. Priming with BBIBP-CorV induced less class-switching among spike-binding memory B cells and the highest antigen-specific T cell responses in heterologous combinations. These were generally more immunogenic in terms of specific antibodies and cellular responses compared to homologous regimens. Finally, single-cell analysis of 754 samples revealed specific B and T cell signatures of the vaccination regimens, indicating distinctive differences in the immune responses. These data provide new insights on the immunological effects of COVID-19 vaccine combinations and a framework for the design of improved vaccination strategies for other pathogens and cancer.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



This well-written manuscript determined the humoral and cellular immune profiles induced by sixteen different homologous and heterologous immunization regimens, using five different COVID-19 vaccines spanning three technologies (inactivated vaccines, mRNA vaccines, and adenoviral vectored vaccines). Overall, the methodologies were appropriate and the conclusions were supported by data.

The deployment of vaccines is regarded as one of the most important ways to combat the COVID-19 pandemic. Up to now, numerous homologous prime-boost immunization strategies showed robust antigen-specific immune responses to protect against SARS-CoV-2. Recently, heterologous/sequential prime-boost vaccination regimens showed optimized protection. In this study, a head-to-head comparison of immune profiles induced by 16 different homologous or heterologous prime-boost regimens was conducted. Generally, heterologous immunization showed more immunogenic than homologous regimens. Especially, their data showed that the administration of mRNA-1273 as a booster improved immunogenicity in all assessed vaccine protocols, and a primer of BBIBP showed higher T cell responses in heterologous combinations. In addition, the immune signatures of T cells and B cells were uncovered in positive “responders” of vaccines. Their data is valuable in guiding the design of clinical trials measuring the vaccine effectiveness of these heterologous regimens.

A major limitation of this study is that the real-world protective efficacy of these different regimens against SARS-CoV-2 infection or prevention of severe morbidity/ hospitalization was not evaluated. The follow-up of this cohort will provide more valuable scientific information for policymakers. In addition, since many countries have conducted the third time of inoculation, the different booster effects of vaccine platforms are waiting to be determined in the future.

In this study, their data support that the order of vaccine inoculation in heterologous regimens is important in shaping the immune landscape. However, it was not directly or carefully compared. According to their study design, there are three couples, including “AZD prime-Sput26 boost VS Sput26 prime-AZD boost”, “BBIBP prime-AZD boost VS AZD prime-BBIBP boost”, and “BBIBP prime-Sput26 boost VS Sput26 prime-BBIBP boost” could be compared, this data might be valuable in designing vaccines against not only COVID-19 but also other infectious diseases as well as cancer.

In addition, the baseline of immune responses of this cohort is lacking. The “Exclusion criteria” include “having had COVID-19 (symptomatic or asymptomatic) or a positive anti-nucleocapsid IgG via ELISA on T1 (except for those subjects that had been vaccinated with BBIBP as the first dose)”. But how to completely rule out the possibility of historical infection especially asymptomatic infection without clinical tests using serum and/or qRT-PCR samples? Thus, the baseline samples should be taken before the 1st immunization. I understand this difficulty but I would recommend to take baseline samples in future study designs.

Overall, this manuscript provided useful information in designing clinical trials measuring the vaccine effectiveness of heterologous regimens.

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