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Authors: L Liu et al.

Link to paper: https://chemrxiv.org/articles/A_Translatable_Subunit_Nanovaccine_for_COVID-19/12301157/1

Journal/ Pre-Print: ChemRxiv preprint

Tags: Immunology/Immunity, Cell Biology, Inflammation, Vaccines

Research Highlights 

1. Nanovaccine elicits a potent humoral response compared to Alum adjuvant control, inducing both IgG and IgA against S1 subunit of SARS-CoV2, in BALB/c mice.

2. Nanovaccine activates both CD4+ and CD8+ T cell responses (efficient cellular immunity through use of high molecular weight TLR agonists) to express significantly greater amounts of IFN-gamma and TNF-alpha compared to the alum control, in BALB/c mice.

3. Serum from nanovaccine-immunised BALB/c mice neutralised live SARS-Cov2 virus in Vero cells. (In vitro data not shown)

Summary

This study describes a novel nanovaccine candidate; cationic liposomes loaded with CpG ODN (TLR9 agonist), monophosphoryl lipid A (TLR4 agonist) and the SARS-CoV2 S1 subunit. The authors report that a subunit nanovaccine elicits humoral and cellular immune responses in mice. Specifically, BALB/c mice vaccinated with the nanovaccine observe higher IgG and IgA titres compared to control mice, up to 65 days post initial vaccination. The authors also describe nanovaccine induced activation of both CD4+ and CD8+ T cells, with significantly higher expression of IFN-gamma and TNF-alpha versus controls. Finally, the authors claim that serum from vaccinated mice neutralises SARS-CoV2 infection in Vero cells (data not shown), suggesting antibodies induced by the vaccine are neutralising and specific to SARS-CoV2.

Impact for SARS-CoV2/COVID19 research efforts

Develop a vaccine for SARS-CoV2/COVID19

· Describes a subunit nanovaccine, comprising; cationic liposome with TLR agonists as adjuvants and SARS-CoV2 S1 subunit

· Nanovacine elicits cellular and humoral immune responses in BALB/c mice

· Report that serum from vaccinated mice neutralises live SARS-CoV2 in vitro, in Vero cells. (Data missing from paper) (No in vivo viral challenge currently)

· Demonstrates strengths of a liposome delivery vehicle and benefits of TLR agonist adjuvants (promoting cellular immunity) in vaccine development.

· Paper focuses on vaccine design more so than role of vaccine in clearing SARS-CoV2

Noteworthy role of TLR agonists as an adjuvant causing effective cellular immunity

Study Type

· In vitro study

· In vivo study (e.g. mouse, NHP)

Strengths and limitations of the paper

Novelty:

This nanovaccine induces both humoral and cellular responses in vivo, and serum from the vaccinated mice neutralises SARS-Cov2 in vitro.

(In previous coronavirus outbreaks, cellular immunity reported to last up to 6-11 years, while infected individuals only retained antibodies against virus for ~1year)

Paper focusing on immune response to cationic liposomes as delivery vehicles (2012, see link below) report similar immunological findings, thus decreasing novelty and suggesting liposome is largely responsible for certain immunological observations. Lui et al. 2020 does however develop observations, recording an S1-specific IgA increase in nanovaccine immunised mice (novel) o 2012 study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277439/

Standing in the field:

Over 100 vaccines against SARS-CoV2 in R&D; around 20 focusing on protein vaccines. Limited information available concerning number and details concerning subunit vaccines R&D.

From available literature, this paper is one of the first subunit vaccines against SARS-CoV2.

Previous SARS-CoV subunit vaccines have been shown to effectively neutralise SARS-CoV during infection. Similar hope here.

Appropriate statistics:

Yes, ANOVA used throughout.

Viral model used:

SARS-CoV2 strain CZ01 isolated from patients.

Translatability:

Nanovaccine is in preliminary stages of development. While demonstrated to induce both neutralising antibodies and T cell responses in BALB/c mice, further research is required to assess safety of vaccine in vivo and determine its efficacy.

FDA approved cationic liposome vectors for drug delivery exist and may be potentially repurposed (E.G. AmBisome® and Doxil®) as viral vectors, however unclear how successful/realistic this may be. AmBisome® is primarily for antifungals and Doxil® for chemotherapy.

Main limitations:

· CRITICAL DATA/FOCUS OF PAPER: The data regarding SARS-CoV2 neutralisation in vitro is completely lacking, thus there is no validation to their claim that the serum from vaccinated mice neutralises SARS-CoV2. Creates suspicion story/data might not be as straight forward as it is presented.

· No mention of safety/ adverse effects of the vaccine in the mice.

· Antibody titres appear to have decreased between days 42 and 65. It would be useful to see titres beyond day 65.

· Some figures and methods are not entirely clear (E.G. figure 3D; Lacking units and inconsistencies in sample collection dates across conditions)

· Certain controls missing (E.G. No cationic liposome alone) and data contextualisation missing (E.G. Fold increase of S1-specific antigen IgA in nasopharynx mucus in immunised BALB/c mice not compared to other mucosal sites)

· No live viral challenge in vivo.