Benefits of heterotypic vaccination against variants of SARS-CoV-2

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A recent study posted to the bioRxiv* preprint server evaluated the antibody responses against the newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron variant upon heterotypic vaccination in animal models.

Study: Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2. Image Credit: spaxiax/Shutterstock


The coronavirus disease 2019 (COVID-19) pandemic is still a significant public health crisis with the emergence of novel variants featuring enhanced infectivity, transmissibility, and immune resistance. The recently emerged SARS-CoV-2Omicron variant of concern (VOC) has rapidly become the predominant variant in circulation. The initial spread of the Omicron variant in its BA.1 form was followed and rapidly eclipsed by the BA.2 sub-lineage, classified as a VOC by the World Health Organization (WHO).

Reports suggest that the ongoing waves of COVID-19 are driven by the BA.2 variant. One of the most staggering features of the Omicron variant and its sub-variants is the high number of mutations in the spike (S) protein, which the therapeutic antibodies and vaccines target. Hence, the Omicron variant extensively evades vaccine-induced immunity, given that vaccines are designed based on the wild-type (WT) SARS-CoV-2. These observations prompted calls for creating vaccines specific to SARS-CoV-2 variants.

The study

The researchers developed WT and variant-specific messenger ribonucleic acid (mRNA) vaccines encapsulated by lipid nanoparticles (LNP) and immunized mice to assess the antibody responses in the current study.

The LNP-mRNA vaccine was synthesized by dissolving the lipid mixture in ethanol and mixing it with target mRNA (WT or variant-specific). C57BL/6Ncr mice were immunized in two sets; the first set of mice completed vaccination with two doses of either WT, B.1.351, or B.1.617 LNP-mRNAs. The second set received two WT LN-mRNA doses and either WT or BA.1 boosters. Retro-orbital blood was obtained from animals at different time points: two weeks after the second dose (day 35 post-immunization), pre-booster (day 166), and two weeks after booster vaccination (day 180).

First, mice vaccinated with WT, B.1.351, or B.1.617 vaccines were profiled. Samples collected from these mice demonstrated significant antibody responses against BA.2 variant; however, those immunized with B.1.351 or B.1.617-specific LNP-mRNAs exhibited higher binding and neutralizing titers than WT LNP-mRNA-vaccinated mice, although the difference was insignificant.

Mutations such as K417N, N501Y, and D614G are common to BA.2 and B.1.351 variants, and G142D, D614G, and P681R substitutions are shared between BA.2 and B.1.617 variants, explaining why the variant-specific vaccines elicited higher antibody responses than WT vaccine. Moreover, all three groups exhibited nearly equal antibody responses against the two Omicron sublineages, indicating that the reactivity to heterotypic vaccination was similar.

The two Omicron sub-variants share 21 mutations and differ at 25 sites. These differences are concerning and question the potency of heterotypic vaccination against the BA.2 variant. To this end, they profiled antibody responses induced by a BA.1-specific LNP-mRNA against the BA.2 variant.

Mice were immunized with WT LNP-mRNA in the primary series and completed (homologous) WT or (heterologous) BA.1 booster vaccination. The booster effect was distinct and better with BA.1-specific LNP-mRNA than WT LNP-mRNA against both sublineages. The antibody titers increased 293-fold against the BA.1 variant and 137-fold against the BA.2 variant when boosted with BA.2 LNP-mRNA. The increase in antibody titers with homologous booster was 62-fold against the BA.1 variant and 48-fold against the BA.2 variant. The booster effect (both homologous and heterologous) was weaker against the BA.2 variant than the BA.1 variant and was more evident with BA.1 LNP-mRNA. Moreover, the antibody titers were similar for both sub-variants post-boosting. The observed differences were due to the low antibody titers against the BA.2 variant before the booster vaccination, albeit the pre-booster difference was insignificant statistically.

The neutralizing titers post-boosting increased by 18-fold with the WT booster and 63-fold with the BA.1 booster. Notably, the heterotypic BA.1 vaccine booster was more efficient at elevating the neutralizing titers than the WT vaccine booster.


The current study observed the antibody waning over time in line with several reports. The authors noted that variant-specific LNP-mRNA vaccines exhibited benefits over WT LNP-mRNA candidates to varying degrees. The BA.1 LNP-mRNA vaccine significantly boosted immune responses against the Delta and Omicron variants in mice vaccinated with the WT vaccine (in primary series). The advantages of heterotypic vaccination (WT and variant-specific vaccines) were remarkable.

These findings indicated that the WT vaccine in the primary series and the heterotypic BA.1-specific vaccine in the booster series might confer robust immunity against the Omicron BA.2 variant.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

Source: News Medical

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