Nanoparticle (SpFN) vaccine candidate elicits multifactorial cellular immune responses against SARS-CoV-2 in vivo

Researchers have developed a promising new anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate that utilizes nanotechnology and shows robust, long-lived immunity in mouse models.

According to this new study, the vaccine enhanced the recruitment of APCs (antigen-presenting cells), increased polyfunctional spike-specific T cells, with a bias towards TH1 responses, IFN-γ and TNFα as the dominant cytokines, and more robust SARS-CoV-2 spike-specific recall response and presented broad protection against other coronavirus strains. The researchers have performed a thorough study of the vaccine-evoked innate and adaptive immune responses in mice against SARS-CoV-2.

Their vaccine, detailed in a paper published recently on the bioRxiv* preprint server, contains a novel particulate nanoparticle, SpFN combined with a potent adjuvant.

The study

The messenger RNA-based vaccines and recombinant adenovirus vectored vaccines approved for emergency use have demonstrated potent efficacy and unprecedented deployment speed. However, the researchers explain that there is a need for 1) precision vaccine design that may offer improved efficacy to different demographic groups; 2) vaccines that induce durable, long-term immune responses; and 3) a multivalent strategy that protects against emerging variants of SARS-CoV-2 as well as multiple coronavirus (CoV) species that may jump the species barrier to humans in future.

To fill these gaps, the team recently developed a SARS-CoV-2 sub-unit vaccine based on the ferritin nanoparticle platform that displays a pre-fusion stabilized viral spike protein on its surface.

The study’s main aim was “to utilize a unique liposomal adjuvant formulation and a common adjuvant, aluminium hydroxide gel, with a novel particulate antigen, SpFN, to understand the early innate immune responses at the site of vaccination.”

The vaccine candidate

They informed that ferritin, a naturally occurring, ubiquitous, iron-carrying protein that self-oligomerizes into a 24-unit spherical particle, is currently evaluated as a vaccine platform for influenza in two phase 1 clinical trials (NCT03186781, NCT03814720) with two further trials in the recruitment phase for Epstein Barr virus (NCT04645147) and Influenza H10 (NCT04579250).

The researchers genetically linked the modified and stabilized prefusion-spike protein of the Wuhan-Hu-1 strain of SARS-CoV-2, to form a ferritin-fusion recombinant protein, which naturally forms a Spike-Ferritin nanoparticle (SpFN).

They then formulated it with either of the two distinct adjuvants used in this study: 1) Army Liposome Formulation containing the saponin, QS-21(ALFQ), and 2) Aluminum Hydroxide gel (Alhydrogel®) (AH).

Notably, the vaccine SpFN+ALFQ is currently in phase 1 clinical trial in the United States, sponsored by the U.S. Army (ClinicalTrials.gov Identifier: NCT04784767).

Important observations

In this study, the researchers showed for the first time the effect of adjuvant design on antigen-presenting cell (APC) recruitment to the draining lymph nodes (dLNs) and its impact on a SARS-CoV-2 vaccine platform.

They demonstrated a comparison between the SpFN formulated with ALFQ (SpFN+ALFQ) and the SpFN formulated with AH (SpFN+AH). They observed robust and sustained recruitment and activation of classical and non-classical APCs in SpFN+ALFQ. The APC response to SpFN+ALFQ was characterized by conventional type 1 and type 2 dendritic cells (cDC1 and cDC2) with upregulated costimulatory molecules necessary for T cells engagement and differentiation in contrast to SpFN+AH. Intriguingly, they observed that this was associated with a potent TH1-biased cellular response and highly functional spike-specific memory T cells. This study also presented a detailed cytokine profiling.

The researchers noted that, strikingly, vaccination with SpFN+ALFQ resulted in spike-specific CD8+ T cells that established a memory pool.

They identified eleven SARS-CoV-2 T cell epitopes in C57BL/6 mice vaccinated with SpFN+ALFQ that mapped to the spike protein. They also found that the most dominant and immunogenic SARS-CoV-2 spike epitope begins in the spike’s receptor-binding domain (VNFNFNGL; aa 539-546).

Using an MHC class I tetramer, the researchers identified murine Kb restricted SARS-CoV-2 specific memory CD8+ T cells recognizing an eight amino acid sequence (amino acids 539-546; VNFNFNGL) of the SARS-CoV2 spike protein that is conserved in the SARS-CoV spike protein.

This study is the first to report the expansion of vaccine-induced SARS-CoV-2 Kb-spike(539-546) -specific polyfunctional CD8+T cells in mice that also exhibited increased killing of peptide-pulsed target cells in an in vitro cytotoxic T cell assay.”

Importantly, the researchers highlighted in this study that the adjuvant determines the quality and the quantity of early innate responses, which sets the stage for downstream adaptive immune responses.

These findings have demonstrated a novel vaccine platform for SAR-CoV-2 that leverages the innate immune response to induce potent memory-specific antiviral T cells.

By employing a strategy of sampling immunologically relevant tissues temporally and spatially proximal to vaccination, we show that the SpFN vaccine potentiates innate sensing and mobilizes the cellular drivers of a multifactorial immune response,” say the researchers.

*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:
  • Joshua M. Carmen, Shikha Shrivastava, Zhongyan Lu, Alexander Anderson, Elaine B. Morrison, Rajeshwer S. Sankhala, Wei-Hung Chen, William C. Chang, Jessica S. Bolton, Gary R. Matyas, Nelson L. Michael, M. Gordon Joyce, Kayvon Modjarrad, Jeffrey R. Currier, Elke Bergmann-Leitner, Allison M.W. Malloy, Mangala Rao. A spike-ferritin nanoparticle vaccine induces robust innate immune activity and drives polyfunctional SARS-CoV-2-specific T cells. bioRxiv preprint server 2021.04.28.441763; doi: https://doi.org/10.1101/2021.04.28.441763, https://www.biorxiv.org/content/10.1101/2021.04.28.441763v1  
Dr. Ramya Dwivedi

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.

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