Variations in the neutralization of SARS-CoV-2 variants in vaccinated mice and primates

Clinical Trials & Research

In a recent study posted to the bioRxiv* preprint server, researchers demonstrated the variations in the neutralizing antibody (NAb) responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in humans, non-human primates (NHPs), and mice against the SARS-CoV-2 variants of concern (VOCs).

Study: Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice. Image Credit: Hugethank/Shutterstock

Following the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 in late 2019, several vaccines have been developed to mitigate the spread of the infection. Many of these vaccines are now clinically authorized for use in humans. Real-world evidence of vaccine-induced Ab responses against the emerging SARS-CoV-2 VOCs is crucial in devising public health policies and future vaccine candidates.

Before clinical trials involving humans, potential vaccine candidates are tested in small mammals such as mice and NHPs. Serum NAb titers in NHPs and humans demonstrate significant correlates of protection from SARS-CoV-2 infection. Further, they also shed light on the immune evasion associated with the SARS-CoV-2 VOCs.

About the study

In the present study, the researchers compared the NAb responses triggered by the COVID-19 vaccinations in mice, humans, and NHPs.

The BALB/c mice were immunized with three different AddaVax-adjuvanted protein subunit immunogens; a ‘2P’ spike (S), receptor-binding domain-nanoparticle (RBD-NP), and HexaPro S. Neutralizing activity of sera samples collected at weeks two, five, and eight were assessed employing single-round vesicular stomatitis virus (VSV) pseudotyped with SARS-CoV-2 Gamma, Beta, and G614 Ss in human embryonic kidney 293T (HEK293T)/ angiotensin-converting enzyme 215 (ACE215) and VeroE6/ transmembrane protease serine 214 (TMPRSS214) cells.


The results indicated that following two weeks of priming with the three immunogens, only RBD-NP induced detectable serum NAbs in mice whereas only AS03-adjuvanted HexaPro S elicited NAbs in NHPs. Two weeks after priming, the neutralization potency of RBD-NP-induced sera was similar and 1.3 times lower towards SARS-CoV-2 Gamma, and two and 2.9 times lower towards SARS-CoV-2 Beta compared to G614 using VeroE6-TMPRSS2, and HEK293T-ACE2 cells, respectively.

Robust NAb responses were induced by all three immunogens two weeks following the booster dose. Five weeks after boosting, the neutralization potency of RBD-NP-induced sera of mice was 2.4 times higher for Beta and 1.2 times lower for Gamma, S ‘2P’-elicited sera were 1.5 times lower for Beta and two times higher for Gamma, and HexaPro S-elicited sera were 1.2 times lower for Beta and 1.4 times higher for Gamma than G614 using VeroE6-TMPRSS2 cells, respectively. These results were in line with those from the assays using HEK293T-ACE2 cells, except NAb responses induced by HexaPro S were five times and 2.8 times lower against Beta and Gamma, respectively, compared to G614.

BALB/c mice immunized twice with the messenger ribonucleic acid (mRNA)-127316 demonstrated 2.3 times lower neutralizing activity against Gamma and Beta variant pseudoviruses (PV), respectively, relative to G614 using A549/ACE2/TMPRSS2 cells at two weeks post-boost. Further, 129S2 and K18-hACE2 transgenic mice vaccinated twice with mRNA-1273 demonstrated 1.8 and 1.25 times higher Beta variant neutralization potency, respectively, than G614.   

The NAb titers of all sera samples of the pigtail and rhesus macaques immunized with HexaPro S protein subunit or RBD-NP vaccines were lower than the immunogen-matched mice titers, thus suggesting that vaccine-induced NAb responses in NHPs are substantially affected by SARS-CoV-2 VOCs such as Beta and Gamma, compared to the BALB/c mice.

The NAb titers of individuals vaccinated with Moderna mRNA-1273 or Pfizer/BioNTech indicated the reductions in neutralization potency against SARS-CoV-2 VOCs such as Gamma and Beta compared to G614 was similar to that of the NHP data and far higher than that of BALB/c mice.

The neutralizing activity of RBD-NP primed sera samples from mice at the eighth week was almost unchanged towards Gamma and Beta PVs in VeroE6/TMPRSS2 cells compared to G614. The neutralizing activity of the sera samples from BALB/c mice vaccinated with mRNA-1273 was attenuated by 3.3 times against Beta compared to G614 at eight weeks following vaccination. In contrast, mice immunized with HexaPro S demonstrated six times and 1.3 times lower neutralization capacity against Beta and Gamma PVs, respectively, compared to G614, resembling the human and NHP data.


The study findings show that BALB/c mice vaccinated with immunogens such as RBD-NP, ‘2P’ S, and HexaPro S do not accurately indicate the actual potency and breadth of vaccine-induced NAb responses against SARS-CoV-2 VOCs relative to that in humans or NHPs. These variations in the activity of NAbs among mice models and primates might be because of the variations in immune repertoires between them.

However, recent studies demonstrate that the NAb responses induced by the ChAd-SARS-CoV-2-S vaccine delivered intranasally in transgenic mice and SARS-CoV-2 S messenger ribonucleic acid-lipid NP (SARS-CoV-2 mRNA-LNP) injected intramuscularly in BALB/c mice were comparable with the expected human response to G614 and Beta. Hence, further investigations are warranted to understand the generalizability and immunological basis of the present findings.

Overall, the study suggests that although the mice model is a time- and cost-effective method for assessing the immunogenic potential of vaccine candidates, other animal models might be appropriate to investigate the immune evasion of future SARS-CoV-2 VOCs because of their variations in NAb responses.   

*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:

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