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Review 1: "Heterologous Booster with a Novel Formulation Containing Glycosylated Trimeric S protein is Effective against Omicron"

While suggesting minor clarifications, the reviewer considered the study valuable, emphasizing the significant immune response elicited by mRNA-based and S protein-based vaccines against Omicron variants. Overall, it as an important contribution to COVID-19 vaccine research.

Published onJul 02, 2024
Review 1: "Heterologous Booster with a Novel Formulation Containing Glycosylated Trimeric S protein is Effective against Omicron"
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Heterologous booster with a novel formulation containing glycosylated trimeric S protein is effective against Omicron
Heterologous booster with a novel formulation containing glycosylated trimeric S protein is effective against Omicron

Abstract In this study, we evaluated the efficacy of a heterologous three-dose vaccination schedule against the Omicron BA.1 SARS-CoV-2 variant infection using a mouse intranasal challenge model. The vaccination schedules tested in this study consisted of a primary series of 2 doses covered by two commercial vaccines: an mRNA-based vaccine (mRNA1273) or a non-replicative vector-based vaccine (AZD1222/ChAdOx1, hereafter referred to as AZD1222). These were followed by a heterologous booster dose using one of the two vaccine candidates previously designed by us: one containing the glycosylated and trimeric spike protein (S) from the ancestral virus (SW-Vac 2μg), and the other from the Delta variant of SARS-CoV-2 (SD-Vac 2μg), both formulated with Alhydrogel as an adjuvant. For comparison purposes, homologous three-dose schedules of the commercial vaccines were used. The mRNA-based vaccine, whether used in heterologous or homologous schedules, demonstrated the best performance, significantly increasing both humoral and cellular immune responses. In contrast, for the schedules that included the AZD1222 vaccine as the primary series, the heterologous schemes showed superior immunological outcomes compared to the homologous 3-dose AZD1222 regimen. For these schemes no differences were observed in the immune response obtained when SW-Vac 2μg or SD-Vac 2μg were used as a booster dose. Neutralizing antibody levels against Omicron BA.1 were low, especially for the schedules using AZD1222. However, a robust Th1 profile, known to be crucial for protection, was observed, particularly for the heterologous schemes that included AZD1222. All the tested schedules were capable of inducing populations of CD4 T effector, memory, and follicular helper T lymphocytes. It is important to highlight that all the evaluated schedules demonstrated a satisfactory safety profile and induced multiple immunological markers of protection. Although the levels of these markers were different among the tested schedules, they appear to complement each other in conferring protection against intranasal challenge with Omicron BA.1 in K18-hACE2 mice. In summary, the results highlight the potential of using the S protein (either ancestral Wuhan or Delta variant)-based vaccine formulation as heterologous boosters in the management of COVID-19, particularly for certain commercial vaccines currently in use.

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.


Review: This study provides valuable insights into the potential of heterologous vaccination schedules, especially involving the mRNA-based vaccine and the S protein-based vaccines, in offering protection against emerging SARS-CoV-2 variants like Omicron BA.1. It presents a comprehensive evaluation of the immunogenicity and efficacy of various vaccination schedules against the Omicron BA.1 SARS-CoV-2 variant. Researchers compared heterologous and homologous vaccination schedules of mRNA-1273, AZD1222 and SD/SW-Vac. The data in this study provide insights into the immune response elicited by different vaccine combinations. The use of K18-hACE2 mice and the focus on both humoral and cellular immunity are particularly noteworthy. The study's exploration of mRNA-based, protein-based and vector-based vaccines, with the inclusion of heterologous boosters, adds depth to the current understanding of vaccine efficacy. Consideration of additional vaccine candidates, such as Omicron adapted vaccines as boosters could provide a more comprehensive view of the potential vaccination strategies. Overall, this study is a valuable addition to the growing body of research on COVID-19 vaccines.

Comments that may help enhance clarity and quality of this study are listed below:

  1. It remains unknown how SW/SD specific IgG is determined. Are they determined using single dilution point? What is the dilution factor used in Fig. 1 and Fig. S1?

  2. In Figure 5, prior to viral challenge, the vaccination procedure itself led to more evident body weight changes than viral challenges. It remains unclear whether the body weight loss seen in SD-Vac group is due to viral challenge or SD-Vac vaccination.

  3. Figure 4 quantifies the cell numbers of CD4 sub-populations after spike protein stimulation. It is beneficial to describe the details about the initial cell number before stimulation and total number of cells counted in flowcytometry in methods or figure legends.

  4. Figure S2 is missing.

  5. In figure 1B-1C, it is intriguing to see the AZD1222 x 3 showed a lower antibody titer than AZD1222 x 2. Standardization of all experiment procedures would facilitate comparison between two experiment datasets. Alternatively, authors can compare all relevant samples in one experiment.

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