Intranasal vaccine shows broad protection against SARS-CoV-2 variants

This innovative vaccine harnesses the power of a single dose to provide powerful protection against current and future COVID-19 threats.

study: A single-dose intranasal live-attenuated, codon-non-optimized vaccine provides broad protection against SARS-CoV-2 and its variants. Image credit: Phonlamai Photo / Shutterstock.com

According to a recently published study, Nature Communications Decided Efficacy A codon-optimized intranasal live-attenuated vaccine (LAV) against current and future variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

New COVID-19 vaccines needed to fight new variants and boost immunity

Although therapeutic strategies for COVID-19 have been developed, vaccination remains the most effective way to prevent the disease. Currently available COVID-19 vaccines are typically based on SARS-CoV-2. Spike ProteinThe receptor binding domain (RBD) is targeted, Neutralizing antibodies.

While most COVID-19 vaccines have been protective against early SARS-CoV-2 variants of concern, this protection has declined sharply with the emergence of new variants with mutated RBDs. For example, SARS-CoV-2 omicron and related variants continue to infect recovered and vaccinated individuals. Furthermore, spike mutations reduce susceptibility to antibody neutralization.

Therefore, it is important to develop new vaccines that induce broadly neutralizing antibodies and are effective against multiple variants, including those that may emerge in the future. LAV induces strong and long-lasting immune responses, often with just one dose. Because LAV contains essentially the entire virus, the immune response is antigenically broad.

Research findings

Previously, the researchers developed an infectious clone of wild-type (WT) SARS-CoV-2 assembled from five synthetic DNA fragments. In this study, the researchers first used the second and third fragments in the CDO and engineered 31 structures that were not repairable.

Therefore, CDO was restricted to the second fragment, resulting in 28 constructs. The codons in these constructs were changed to the corresponding low- or rare codons. Sixteen constructs were rescued as infectious viruses and assessed for plaque morphology and replication kinetics.

The two attenuated candidates, CDO-4N-1 and CDO-7N-1, produced smaller plaque sizes than WT SARS-CoV-2. Furthermore, Calu-3 and Vero E6 cells infected with CDO-7N-1 and CDO-4N-1 showed reduced virus growth rates compared to those infected with the WT virus.

Hamsters infected with CDO-7N-1 and CDO-4N-1 had lower virus titers in bronchoalveolar lavage fluid (BALF) than those infected with WT virus. Furthermore, animals infected with CDO-4N-1 had milder lung lesions than those infected with WT SARS-CoV-2, while little or no lesions were observed in animals infected with CDO-7N-1.

CDO-7N-1, selected as the lead vaccine candidate, underwent 15 passages in Vero E6 cells. Viruses at passages 1 (P1), P10, and P15 displayed a small-plaque phenotype. Furthermore, the P15 virus showed a similar replication kinetics to the P1 virus. Furthermore, the attenuation properties of CDO-7N-1 were maintained after multiple passages. Alive aisle.

Hamsters were then immunized with CDO-7N-1 via the intranasal route and serum was collected at various time points thereafter, while controls were mock immunized with phosphate-buffered saline (PBS).

CDO-7N-1 induced potent neutralizing antibodies that persisted for up to 90 days. Indeed, specific immunoglobulin G (IgG) responses against various viral proteins were detected in vaccinated animals over a long period of time.

Twenty-eight days later, control and vaccinated animals were challenged with WT SARS-CoV-2. Control animals had high virus titers in BALF and nasal passages, as well as significant pneumonia with mild/moderate olfactory epithelium atrophy. Compared to controls, vaccinated animals had no virus in serum, no/mild pneumonia, and normal nasal turbinate structure.

K18-hACE2 mice were also immunized with CDO-7N-1 or PBS and challenged with WT SARS-CoV-2 21 days later. One week after viral challenge, no virus was detected in the brains and lungs of CDO-7N-1 vaccinated mice, whereas PBS recipients showed high viral replication. CDO-7N-1 recipient lungs showed significantly lower lung inflammation and reduced expression of both proinflammatory chemokines and cytokines compared to PBS recipients.

In a separate experiment, K18-hACE2 mice were vaccinated with the CDO-7N-1 vaccine and challenged 21 days later with SARS-CoV-2 beta, delta, and omicron variants. Mice immunized with CDO-7N-1 were protected from beta/delta infection without experiencing any clinical signs of disease, pulmonary lesions, or detectable virus in the brain, lungs, or nose.

In comparison, PBS recipients infected with the beta/delta mutant developed clinical signs of infection with weight loss and prominent lung lesions. Because the omicron mutant is less virulent in K18-hACE2 mice, no signs of lung lesions or disease were detected in CDO-7N-1 recipients or controls.

Virus-specific neutralizing antibodies against the D614G strain, and beta, delta, and omicron, including XBB.1.5 variants, were identified in the sera of CDO-7N-1-vaccinated hamsters and K18-hACE2 mice.

Cynomolgus macaques were also vaccinated with CDO-7N-1 or PBS control and observed for 60 days after immunization before being euthanized. At 48 hours after immunization, CDO-7N-1 vaccinated animals showed minimal diffuse lymphocytic pulmonary infiltrates, whereas one control and one vaccinated macaque showed no histologic changes.

Haematological and clinical parameters were normal in all macaques. No pathology was observed in other organs of control and vaccinated macaques, although both vaccinated macaques experienced rhinitis. Antibodies to SARS-CoV-2 were detected 14 and 40 days after immunization, and elevated levels of binding and neutralizing antibodies to the spike and RBD were observed in the sera of seven macaques.

CDO-7N-1 induced local mucosal immunity, with high levels of spike-specific IgA observed in most macaques. Strong clusters of differentiation cluster 4 (CD4+) and CD8+ T cell responses were also observed in vaccinated animals, along with increased interferon-γ (IFN-γ) production.

Conclusion

The CDO-7N-1 vaccine was highly immunogenic, provided strong protection against infection in hamsters and mice, and showed good evidence of immunogenicity in macaques. This intranasal live-attenuated CDO vaccine also elicited high levels of neutralizing antibodies and strong T cell responses, including CD4.⁺ and CD8⁺ T cells from a single immunization.

Overall, the antigenically broad immune response elicited by CDO-7N-1 is likely to be effective against new variants that require mutations in multiple proteins to evade vaccine-induced immunity.