Impact of a pan-sarbecovirus dendritic cell targeting vaccine on SARS-CoV-2 variants

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 in Hubei province of China led to catastrophic human as well as economic losses worldwide.

The tremendous efforts of the scientific community helped with the implementation of rapid diagnostic tools, immunological monitoring tools and the development of several vaccines.

Study: Design, immunogenicity and efficacy of a pan-sarbecovirus dendritic cell targeting vaccine.  Image credit: BaLL LunLa / ShutterstockStudy: Design, immunogenicity and efficacy of a pan-sarbecovirus dendritic cell targeting vaccine. Image credit: BaLL LunLa / Shutterstock

SARS-CoV-2, which led to the pandemic with coronavirus disease 2019 (COVID-19), belonged to Sarbecovirus subgenus of Coronaviridae. SARS-CoV-2, like all other zoonotic sarbecoviruses, uses the human angiotensin-converting enzyme 2 (ACE2) receptor to penetrate the cell. SARS-CoV-2 is the third major outbreak of infectious disease in humans caused by zoonotic coronavirus after SARS-CoV-1 in 2002-2003 and Middle Eastern respiratory syndrome coronavirus (MERS-CoV) in 2012.

Currently, the COVID-19 vaccines are based on the delivery of SARS-CoV-2 Spike (S) through various vaccine platforms to elicit antibodies to the S protein, which also includes the receptor binding domain (RBD). These vaccines induce Th1 responses that are restricted to the S epitopes but are not particularly sensitive to elicit CD8 + T cell responses, which are also necessary to control infections.

In addition, pandemic control is threatened by the emergence of several SARS-CoV-2 variants of concern (VOCs) such as B.1.1.7 Alpha, B.1.351 Beta, P.1 Gamma, B.1.617.2 Delta and B.1.1.529 Omicron. These variants have been shown to consist of several specific or shared mutations in the S sequences that enhance their transmissibility and ability to escape the immune response. Several recent studies indicated decreased efficacy of mRNA vaccines against the VOCs as well as reduced efficacy in immunocompromised and elderly individuals. Therefore, new and complementary vaccines administered as a booster or prophylaxis are needed to control the SARS-CoV-2 variants.

Dendritic cells (DC) are a class of immune system controllers that help deliver signals to other immune cells using soluble factors and intercellular interactions. An effective strategy to improve subunit vaccine efficacy while reducing the amount of antigen required may be to target the vaccine antigens to the DCs using surface receptors. This not only helps with the delivery of specific antigens, but also elicits an activation signal that stimulates the immune response without the need for additional immunostimulatory agents.

Previous studies suggested that vaccines targeting various viral antigens against CD40-expressing antigen-presenting cells elicited strong T and B cell responses. Studies have also reported the efficacy of a new generation of subunit vaccines targeting RBD of the SARS-CoV-2 peak protein to the CD40 receptor.

A new study published in the pre-print server bioRxiv* Used and silico approaches to designing a next generation of CD40-targeted vaccine, CD40. CoV2 included new T and B cell epitopes from SARS-CoV-2 and was also homologous to 38 sarbecoviruses, including SARS-CoV-2 VOCs. The study reported the antiviral effect as well as immunogenicity of this vaccine in a preclinical model.

About the study

The study involved the production of the CD40.CoV2 vaccine using expression plasmids via transfection into mammalian CHO-S cells and followed by protein A affinity purification. Infectious stocks of Wuhan / D614 SARS-CoV-2 virus were grown by inoculating Vero E6 cells and collecting supernatants after cytopathic effects were observed.

Subsequently, 8 to 12 week old transgenic mice were injected with CD40.CoV2 vaccine and polyinosine polycytidylic acid (Poly-IC; Oncovir) or Poly-IC alone at three week intervals. They were then infected with SARS-CoV-2 at week 4 and monitored daily for mortality and morbidity. Blood was collected from them on day 2 before vaccination, day 28 before infection and day 40 after vaccination.

The viral load was measured by RT-qPCR along with median tissue culture infectious dose (TCID50). This was followed by antibody measurement, production of specific SARS-CoV-2 antigens, characterization of SARS-COV-2 specific immune responses in convalescent COVID-19 patients, quantification of culture supernatant analytes from convalescent COVID-19 mononuclear blood cells PBMCs) 2 days after CD40.CoV2 vaccine administration and cytotoxicity assay.

Survey results

The results reported four T- and B-cell epitope-enriched regions in the S, N, and M structural proteins of SARS-CoV-2 selected as vaccine regions. The vaccine sequences reported 42 percent and 48 percent CD8 + T cell epitopes for S and N proteins, respectively, while 46 percent and 40 percent were reported for CD4 + 161 T cell epitopes. Two CD4 + T cell epitopes and nine CD8 + T cell epitopes were found to be 100 percent homologous across all sarbecoviruses.

The results also indicated that unvaccinated mice showed significant weight loss as well as the development of symptoms after infection that could lead to death, while vaccinated mice showed no symptoms and none of them died. The viral replication and viral infectious particles were found to be lower in the lungs of vaccinated mice compared to unvaccinated mice.

In addition, CD40.CoV2 vaccine levels were reported to be quite high one week after booster injection in vaccinated mice. The vaccine was also capable of eliciting cross-neutralizing antibody responses to RBD from both the original SARS-CoV-2 strain and the VOCs and S from both SARS-CoV-2 and SARS-CoV-1.

In addition, the CD40.CoV2 vaccine induced significantly higher proliferation of specific CD4 + and CD8 + T cells and CD19 + B cells. The vaccine also stimulated the production of several chemokines and cytokines. The vaccine produced a high amount of cross-reactive SARS-CoV-1 CD4 + and CD8 + T cells. The vaccine was found to induce SARS-CoV-1 and SARS-CoV-2-specific T cell responses, which were found to be strongly correlated for almost all corresponding antigen sequences. The vaccine response was also not affected by RBD mutations by the VOCs and recognized the SARS-CoV-1 epitopes quite well.

The current study therefore shows the urgent need to develop a “pan-sarbecovirus vaccine”. The CD40.CoV2 vaccine involved in the study was found to be quite responsive to the SARS-CoV-2 VOCs and has also shown significant cross-reactivity in both human and mouse models. Further research is needed to develop protein-based vaccines to combat the new SARS-CoV-2 variants as well as future SARS-like coronaviruses.

Limitations

The study had certain limitations. First, there was no characterization of cross-neutralizing antibodies in vaccinated mice against the B.1.1.529 Omicron variant. Second, various VOC challenges in mice were not evaluated. Finally, the T cell responses were determined using samples obtained from recovered individuals instead in vivo preclinical models.

*Important message

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

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