The intranasal vaccine represents an effective broad spectrum vaccine strategy against COVID-19

In a recently published study bioRxiv* Server, researchers evaluated the efficacy of dNS1-RBD, a novel intranasal vaccine against coronavirus disease 2019 (COVID-19).

background

Almost 38 currently used COVID-19 vaccines are administered by intramuscular injection. They offer protection against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly by eliciting neutralizing antibodies (nAbs) that target the viral spike (S) antigen.

Mass vaccination has been effective in reducing symptomatic SARS-CoV-2 infection, hospitalization and deaths. However, SARS-CoV-2 uniquely demonstrates an anatomical escape in the upper respiratory tract (URT), where nAb titers are 200-500 times lower than in the circulatory system, making it impossible to detect the SARS-CoV-2 Completely block infection after peak Vaccine-induced immune response phase is over.

In addition, variants that escape immunity (eg, Omicron) are still emerging, and SARS-CoV-2 has multiple animal host reservoirs (eg, cats, mink, deer). All of these factors make SARS-CoV-2 viable to coexist with humans for many years and pose an ongoing threat. Therefore, there is a need to continuously develop broad-spectrum COVID-19 vaccines that work through different immune mechanisms and routes of administration.

In particular, there is a greater need for vaccines that protect URT locally to respond to SARS-CoV-2 in a timely manner. For example, several vaccines that work via respiratory vaccination are being tested in preclinical animal experiments. For example, one developed by Zhou Xing et al. has demonstrated broad protective efficacy against multiple SARS-CoV-2 variants. With proven broad-spectrum efficacy in preclinical experiments, respiratory mucosal vaccines have become an area of ​​great interest for researchers exploring novel COVID-19 vaccine candidates.

About the study

In the present study, researchers examined the immune response elicited by an intranasal spray vaccine based on the nonstructural protein 1 (NS1)-deleted H1N1 influenza vector carrying the gene encoding the SARS-CoV-2 receptor-binding domain ( RBD) named dNS1 encodes -RBD. This vaccine showed a good safety profile in phase I and phase II clinical trials, but a weak peripheral immune response. It prevented SARS-CoV-2-induced pathological changes without eliciting significant neutralizing antibodies, which differs from the protective mechanism of traditional vaccines.

Because a vaccine could induce a protective immune mechanism through four pathways: innate immunity, trained immunity, cellular immune responses covering URT and LRT, and antibodies directed to RBD, the researchers evaluated the efficacy of dNS1-RBD from all four aspects. The team used ribonucleic acid sequencing (RNA-seq) analysis to study the innate immune response elicited by dNS1-RBD.

They collected 15 samples of mouse lung tissue for RNA-seq analysis. The study group included 12 samples from vaccinated mice collected at 7, 14 and 28 days post-vaccination (dpim). The remaining three samples from unvaccinated mice served as controls. The team harvested lung immune cells and analyzed them at different time points using flow cytometry (FC).

In addition, researchers used principal component analysis (PCA) to examine gene expression levels of genes involved in innate immune signaling and cytokine-related signaling pathways. They also drew heat maps to show differentially expressed genes (DEGs) in the dNS1-RBD compared to the control group.

study results

The primary finding of the study was that dNS1-RBD vaccination helped the host maintain tissue homeostasis that provided pathological protection against SARS-CoV-2 by inducing trained immunity with broad-spectrum antiviral and anti-inflammatory effects. Furthermore, dNS1-RBD activated alveolar macrophages, myeloid dendritic cells and natural killer (NK) cells and altered the chromatin openness of these cells.

Because the gene that controls these cells’ immunity to infection remained open for several months, they remained protected from SARS-CoV-2. dNS1-RBD vaccination also inhibited SARS-CoV-2 copy numbers by approximately 155-fold, 84-fold, and 10-fold on days 1, 3, and 5, respectively. In short, dNS1-RBD altered the anti-SARS-CoV-2 immune response pattern by training immune cells and structural cells to reduce inflammation and confer protection.

Studies have also shown that intranasal immunization is also attenuated Bordetella pertussis provided protection against two influenza A viruses, further underscoring the importance of trained immunity for non-specific protection at higher rates. Another notable effect of the dNS1-RBD vaccine was that it provided good protection within 24 hours. Because it used a truncated NS1, it induced faster and more potent cytokine production. These properties make dNS1-RBD a great emergency vaccine that could be given early during an endemic outbreak to reduce the COVID-19 burden and halt onward transmission of SARS-CoV-2.

Tissue resident memory T (T_rm) cells offer long-lasting and broad immune protection. They are critical in controlling respiratory viral infections and provide timely and stronger protective immunity than circulating T cells. It is of great importance in the context of an asymptomatic or mild SARS-CoV-2 infection. The dNS1-RBD vaccine elicited RBD-specific cellular immune responses in the nasal-associated lymphoid tissue (NALT) and lungs on day five post-vaccination, which lasted for at least six months in the periphery.

Conclusions

The current study highlighted that dNS1-RBD-like intranasal vaccines could act as a booster in heterologous COVID-19 vaccination regimens. Although dNS1-RBD showed the limited potential of viral clearance, it favorably redesigned the immune microenvironment and trained the immune and structural cells to provide adequate protection in the airways. In addition, it helped maintain immune balance between the innate immunity arm and respiratory tissue to mitigate immune-induced tissue injury. Most importantly, it induced broad-spectrum local cellular immunity and trained immunity in the airways, which is beneficial for addressing emerging SARS-COV-2 variants.

*Important NOTE

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