Omicron-based vaccine candidate generated to assess whether immunogenicity could be further improved

In a recent study posted to the bioRxiv* preprint server, researchers used the human adenovirus type 26 vector (Ad26)-based vaccine platform to generate a novel vaccine candidate Ad26.COV2.S.529. They evaluated the novel vaccine’s immunogenicity against the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) Omicron (BA.1).

Study: Immunogenicity of an Ad26-based SARS-CoV-2 Omicron Vaccine in Naïve Mice and SARS-CoV-2 Spike Pre-immune Hamsters. Image Credit: Viacheslav Lopatin/Shutterstock

Omicron has an unprecedented number of mutations in its spike (S) protein that weakens the effect of neutralizing antibodies elicited by natural SARS-CoV-2 infection or vaccination. Recent studies showed that a booster dose with current vaccines, especially a messenger ribonucleic acid (mRNA) vaccine booster (using Wuhan-Hu-1 S as antigen), conferred lesser protection against Omicron infections, and the induced immunity also waned quickly.

About the study

In the current study, researchers developed a vaccine candidate termed Ad26.COV2.S.529, encoding a stabilized Omicron-based S protein resembling ancestral SARS-CoV-2 Wuhan-Hu-1 S protein. They evaluated immunogenicity in naïve mice and pre-immunized hamsters.

To characterize the S expression of Ad26.COV2.S.529 vaccine in vitro, the team transduced A549 cells with CV3-25 and angiotensin-converting enzyme 2 (ACE2)-Fragment, crystallizable (Fc). They showed that CV3-25-S binding in transduced A549 cells with Ad26.COV2.S or Ad26.COV2.S.529 was comparable, and ACE2-Fc fusion protein binding to both S proteins was similar.

Notably, the CV3-25 antibody binds to the same conserved region between the Wuhan Hu-1 and BA.1 S protein; likewise, ACE2-binding affinity is similar between these two S proteins.

They limited the study analyses to the two most prevalent SARS-CoV-2 VOCs worldwide – Delta (B.1.617.2) and Omicron. They immunized naïve mice with 108, 109, 1010 viral particles (vp) of Ad26.COV2.S, Ad26.COV2.S.529 or 1010 vp of Ad26 empty mock control vector.

Similarly, they immunized hamsters with 107 vp Ad26NCOV006, which encodes the non-stabilized WuhanHu-1 S protein, and the control group with 107 vp of Ad26.empty mock control vector. Six weeks later, the hamsters received vaccination with 1010 vp of Ad26.COV2.S, Ad26.COV2.S.529 or Ad26.control vector.

The sera from the test animals (mice and hamsters) were collected four weeks after immunization. The researchers used pseudovirion neutralization assay (psVNA) to evaluate SARS-CoV-2 Delta and Omicron S neutralization titers.

Study findings

Previous studies have shown that Omicron S-based mRNA vaccines elicited similar neutralizing antibody levels against Omicron, compared to the original Wuhan-Hu-1 S-based mRNA vaccine in non-human primates (NHPs) immunized with two doses of an mRNA vaccine.

In the present study, the authors made some contrasting observations. They observed that in naïve mice, Ad26.COV2.S.529 but not Ad26.COV2.S induced robust Omicron S neutralizing titers. In addition, Ad26.COV2.S.529 elicited increased Omicron S neutralizing titers in pre-immune hamsters whereas Ad26.COV2.S did not.

The authors have also previously demonstrated that in pre-immune NHPs, a heterologous booster vaccination with an Ad26 vector-based vaccine (Ad26.COV2.S.351) expressing a stabilized Beta-based S protein in more than seven months after Ad26.COV2.S vaccination elicited 2.9-fold higher Beta psVNA titers than homologous vaccination with the Ad26.COV2.S.

However, there is no data evidence for these findings. Hence, it is unknown whether these differences are related to the magnitude of immune responses elicited by previous immunizations, the dosage of vaccinations with the Wuhan-Hu-1 S-based vaccine administered (before receiving the Omicron S-based vaccine), the vaccine platform, or the NHP used for the study.

A study conducted in South Africa during the Omicron-induced pandemic wave has shown immunization with a homologous booster dose of Ad26.COV2.S six to nine months after primary vaccination provided more than 80% protection against hospitalization in Omicron cases. These study findings revealed that although vaccine-induced protection conferred low Omicron neutralizing antibody titers, it sustained for a longer duration as the vaccine-elicited cellular immunity and generated non-neutralizing antibodies with Fc-functions across SARS-CoV-2 variants.

Subsequently, post four weeks of immunization with Ad26.COV2.S, Omicron-neutralizing antibodies were not detected in either naïve mice or hamsters. In vitro studies showed that the expression of S is similar after transduction with both Ad26.COV2.S and Ad26.COV2.S.529. This finding suggested that boosting pre-existing neutralizing epitope-specific memory B cells (although low in number) or de novo induction of B cells could effectively generate antibodies to neutralize Omicron.

While Ad26.COV2.S.529 vaccination resulted in similar Delta S neutralization titers as Ad26.COV2.S in pre-immune hamsters, the Delta neutralizing titers were extremely low in Ad26.COV2.S.529 vaccinated naïve mice. Together, these findings indicated that compared to homologous S protein immunization, heterologous immunization with Ad26.COV2.S.529 induced broadly neutralizing antibody response in animals with pre-existing immunity to Wuhan Hu-1 S.


Overall, the vaccine candidate developed in the current study elicited robust Omicron S neutralizing titers in pre-immune hamsters and naïve mice. This finding is in agreement with previous studies conducted on  Omicron-based RNA vaccines in naïve NHPs.

*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:
  • Swart, M. et al. (2022) "Immunogenicity of an Ad26-based SARS-CoV-2 Omicron Vaccine in Naïve Mice and SARS-CoV-2 Spike Pre-immune Hamsters". bioRxiv. doi: 10.1101/2022.03.04.482636.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

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Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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