Intranasally administered SARS-CoV-2 RBD-based nanoparticle vaccine provides protection against lung pathology and viral load

In a recent study published in Scientific Reports, researchers working at Ohio State University in the United States of America (USA) developed an intranasal subunit vaccine.

An intranasal vaccine comprising SARS-CoV-2 spike receptor-binding domain protein entrapped in mannose-conjugated chitosan nanoparticle provides protection in hamsters
Study: An intranasal vaccine comprising SARS-CoV-2 spike receptor-binding domain protein entrapped in mannose-conjugated chitosan nanoparticle provides protection in hamsters. Image Credit: Skylines/Shutterstock.com

Named the NARUVAX-C19/Nano, the vaccine is based on the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein entrapped in mannose-conjugated chitosan nanoparticles (NP). 

As an adjuvant, they added a toll-like receptor 9 (TLR-9) agonist, CpG55.2, in this vaccine to facilitate the elicitation of cellular immune responses. Next, they tested NARUVAX-C19/Nano for immunogenicity, efficacy, and ability to prevent transmission from vaccinated to naive animals.

Background

Of 368 coronavirus disease 2019 (COVID-19) vaccine candidates developed during the pandemic, only 170 reached human clinical trials.

Subsequently, the World Health Organization (WHO) qualified 11 vaccines based on varied technology platforms, e.g., messenger ribonucleic acid (mRNA), inactivated, viral vector, and protein subunit platforms, for use. Of those 11 vaccines, eight had mucosal route delivery, of which two were subunit vaccines, whereas the remaining were viral vector-based vaccines.

Though vaccination prevented additional waves of disease, the advent of immunity-evading viruses has raised the need for new COVID-19 vaccine approaches, especially those eliciting improved mucosal immunity.

About the study

In the present study, researchers used the standard ionic gelation method to prepare the SARS-CoV-2 S-RBD-based NP-vaccine formulation using mannose-conjugated chitosan nanoparticles, lyophilized and stored at −20 °C until use. They used an intramuscular alum (aluminium hydroxide)-adjuvanted RBD vaccine for comparison. The team used dynamic light scattering (DLS)\photon correlation spectroscopy to evaluate particle size distribution and mean diameter of NP formulations.

The researchers immunized four to-six-week-old female BALB/c mice intranasally with NP-vaccine formulations, only S-RBD antigen, and phosphate buffer saline (PBS) under anesthesia at 21-day intervals. However, they administered the RBD-Alum vaccine intramuscular. They collected blood samples from the test animals 21 days after priming and boosting to assess wild-type SARS-CoV-2's (D614G) RBD-specific secretory immunoglobulin A (IgA), IgG1 and IgG2a, RBD-angiotensin-converting enzyme 2 (ACE2) blocking antibodies and SARS-CoV-2 neutralizing antibody (nAb) titers via enzyme-linked immunosorbent assay (ELISA).

Furthermore, they determined the elicited cellular immunity by measuring cytokine production in mouse splenocytes, presented as the difference (Δ) of cytokine concentrations across samples with and without (5 µg) RBD stimulation. 

Next, the researchers used up to eight-week-old Syrian hamsters (all male) for this vaccine's trial. They immunized test animals, six per group, with NP-vaccine and NP-CpG vaccine (5 µg/dose) intranasally under anesthesia twice at 21-day intervals. 

They challenged hamsters intranasally with SARS-CoV-2 (dosage 1 × 104 50% tissue culture infectious dose (TCID50)/100 µL) under anesthesia 21 days post-boosting. They monitored animals for seven days post-infection (pi). Finally, on days 3 and 7 pi, they euthanized three of six animals from each group to collect their nasal turbinates and lung samples.

Results

The median size of RBD-entrapped mannose-conjugated chitosan NPs was 290 ± 18 nm, with the uptake rate of RBD into NPs being 66.8%. Scanning electron microscopy (SEM) showed that the NP particles were spherical.

One or two doses of intranasal-delivered NP-vaccine induced detectable RBD-specific sIgA in serum and the mice lungs compared to controls, including the S-RBD-only group. On the contrary, its booster dose did not increase these antibodies in any group. 

While a second dose of intramuscular-administered alum-adjuvanted S-RBD vaccine elicited RBD-specific IgG, IgG1, IgG2a as well as RBD-ACE2 blocking and SARS-CoV-2 neutralizing antibodies, intranasal delivered NP-vaccine did not induce detectable levels of any of these in serum. Instead, it induced type 1 T helper (Th1) cells that secreted interferon-gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-α) in response to RBD stimulation. However, only intranasal-delivered NP-CpG vaccine induced IL-17 recall immune responses.

Even though it did not trigger serum-neutralizing antibodies, NP-vaccine provided adequate protection against SARS-CoV-2 infection in vaccinated hamsters. It reduced the viral load in both the upper and lower respiratory tract (URT & LRT) and lung damage, likely by triggering anti-RBD sIgA and T cell immunity.

Notably, cellular immunity elicited by NP-vaccine provided the most protective efficacy.

The addition of CpG55.2 as an adjuvant in NP-vaccine induced increased production of IL-17; however, this did not translate to increased vaccine efficacy. Future studies should evaluate the potential risks and benefits of IL-17 induction with NP-CpG vaccine.

Alum is a highly Th2-biased adjuvant and does not enhance nAb titers compared to immunization with antigen alone. Thus, intramuscular delivered alum-adjuvanted S-RBD vaccine failed to protect against SARS-CoV-2 infection despite inducing systemic humoral and Th2 cellular immune responses.

So far, SARS-CoV-2 load in the URT is the most appropriate proxy for transmission risk, even though multiple factors contribute to increased transmission risk.

NP-immunized hamsters had significantly lower viral titers in nasal turbinates and oropharyngeal swabs than controls; however, once infected, these animals transmitted the virus to naive animals in direct contact. 

Conclusions

In the future, the researchers intend to investigate the efficacy of NARUVAX-C19/Nano in Omicron in light of evidence suggesting that current intramuscular-delivered COVID-19 vaccines offer suboptimal protection against Omicron. 

They also recommended that future studies investigate how alterations in NP-vaccine formulation could increase its systemic immunogenicity and protective efficacy. It is achievable by increasing the efficiency of the incorporation of S-RBD antigen.

Studies could also explore other strategies for improving the efficacy of NP immunization; for example, using it as an intranasal-delivered mucosal booster after intramuscular administration of a protein subunit vaccine NARUVAX-C19. Likewise, loading the NP vaccine with a full spike trimer could be a feasible intervention.

Journal reference:
Neha Mathur

Written by

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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