Clec9A-RBD immunization could trigger robust and sustained systemic and mucosal immune responses against rapidly evolving SARS-CoV-2 variants

In a recent study posted to the bioRxiv* preprint server, researchers assessed the impact of a single-dose dendritic cell vaccine candidate on immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses. Image Credit: creativeneko/Shutterstock
Study: Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses. Image Credit: creativeneko/Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Recently, targeting antigens to dendritic cells (DC) has evolved as an appealing vaccine technique that enhances vaccine efficacy and allows for antigen and dosage sparing. Targeting potential antigen vaccine candidates to type I conventional DC (cDC1) subpopulation-expressed Clec9A has shown promise in pre-clinical investigations, eliciting robust and sustained cellular and humoral immune responses after a single vaccination dose. Clec9A, a C-type lectin-like receptor, functions as a receptor for damage recognition. It was discovered that targeting Clec9A was more effective than targeting DC receptors.

About the study

In the present study, researchers investigated the cellular and humoral immune responses induced by a single systemic dosage of Clec9A-SARS-CoV-2 receptor-binding domain (RBD) antibody construct in mice.

The team determined that 2 µg of poly I:C-adjuvanted Clec9A-RBD elicited the strongest anti-RBD neutralizing titers among adult Balb/c mice after a single dose. A longitudinal examination of the RBD-specific humoral response in mice inoculated with Clec9A-RBD was performed. The neutralizing activity of Clec9A-RBD immunological sera was then evaluated against a panel of 20 sarbecoviruses, including SARS-CoV-2 variants of concern (VOCs), SARS-CoV, and animal CoV belonging to pangolin and bat lineages.

RBD-specific T follicular helper (TFH) cells and germinal centers (GC) B cells elicited were measured. The team then examined the RBD-specific T-cell responses following a single dose of Clec9A-RBD vaccination. The team tested whether a single dosage of Clec9A-RBD administered systemically could induce antigen-specific humoral and cellular responses in lung tissue.

Results

The study results showed that vaccination with an identical antigen dose of poly I:C-adjuvanted non-targeting purified recombinant SARS-CoV-2 RBD did not elicit a considerable anti-RBD immunoglobulin (Ig)-G response. On the other hand, Clec9A-RBD-vaccinated mice elicited detectable antibody titers seven days after immunization, highlighting the efficacy of this targeting technique.

Anti-RBD IgG titers persisted for up to 21 months after vaccination, with a distinct T-helper 1 (TH1) isotype profile. In addition, the antibody-dependent cell-mediated cytotoxicity (ADCC) and neutralizing properties, along with the binding affinity of the immunological sera against the corresponding SARS-CoV-2 ancestral strain, remained over the course of 21 months while gradually increasing over time. These findings strongly imply that Clec9A-RBD-vaccinated animals underwent a prolonged affinity maturation.

The neutralizing activity elicited against most SARS-CoV-2 VOCs rose over time and remained for the duration of the 21-month monitoring timespan, except for the SARS-CoV-2 Omicron variant. Intriguingly, the neutralizing activity observed against clade-1B sarbecoviruses belonging to pangolin and bat species was detectable at all tested time points and grew significantly throughout the 21-month monitoring period. On the other hand, the neutralizing activity against clade-1A sarbecoviruses was low.

The binding affinity of Clec9A-RBD immunological sera against SARS-CoV-2 VOCs rose over time and persisted for 21 months after vaccination. Likewise, ADCC activity reported against SARS-CoV-2 VOCs rose with time and remained elevated 21 months after vaccination. Furthermore, the ADCC activity of immunological sera against Omicron was equivalent to that evaluated against other VOCs.

Antigen-specific spleen TFH cell responses were elicited as early as seven days after Clec9A-RBD vaccination and were still detectable six to 12 months later. These responses were cross-reactive with most SARS-CoV-2 VOCs, such as Omicron. Also, almost two weeks and seven days post-immunization, the team detected GCs in the brachial lymph nodes and spleen, respectively, which survived even after six to 12 months.

Clec9A-RBD-inoculated mice produced considerably more interferon (IFN)-Ɣ-secreting cells when splenocytes were restimulated with RBD peptides. This demonstrated the superior ability to target Clec9A to trigger cellular immunological responses. The comparative abundance of T cells expressing IFN-Ɣ and interleukin (IL)-5 in animals immunized with Clec9A-RBD demonstrated significant TH1-biased cellular responses against corresponding SARS-CoV-2 VOCs and strain, respectively.

Anti-RBD IgG titers with a robust TH1 isotype profile were found in bronchoalveolar lavage (BAL) fluids collected two weeks after Clec9A-RBD vaccination. In addition, the BAL samples exhibited neutralizing as well as ADCC activity against the corresponding ancestral SARS-CoV-2 strain. The detection of RBD-specific GC B cells in the lung is compatible with the RBD-specific antibody production in this tissue.

Conclusion

The study findings showed that targeting SARS-CoV-2 RBD to cDC1s led to robust and extraordinarily long-lasting immune responses after a single vaccination dose. Significantly, the study revealed evidence of affinity development through time, which led to enhanced efficacy and magnitude of the humoral response against a wide range of sarbecovirus family members. The Clec9A targeting technology offers a flexible, plug-and-play vaccine platform that can be swiftly updated to combat rapidly developing variations circulating worldwide. The researchers believe that the human application of this vaccine approach is a feasible and interesting avenue.

*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.

*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:
Bhavana Kunkalikar

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.

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