An experimental intranasal vaccine eliminates the COVID virus in mice.

A team from the Spanish National Research Council ( CSIC ), an agency affiliated with the Ministry of Science, Innovation and Universities, has developed a novel , next-generation, intranasally administered vaccine against the SARS-CoV-2 virus that protects against the most recent variants in preclinical trials conducted in mice.

The work , led by virologist Luis Enjuanes , from the National Center for Biotechnology (CNB-CSIC), has been published in the journal Proceedings of the National Academy of Sciences ( PNAS ) , and demonstrates the safety of the experimental vaccines generated.

Furthermore, researchers have demonstrated its effectiveness in producing sterilizing immunity , that is, immunity capable of completely blocking infection by preventing the virus from replicating in the body . These results have been observed in preclinical experiments conducted on genetically modified rodents with characteristics of the human immune system, known as humanized mice.

This experimental vaccine is based on " defective RNA replicons " from SARS-CoV-2 . "These replicons lack six genes important for pathogenesis and viral spread. They can multiply within the cell, amplifying more than a thousand times , and form particles similar to real viruses , but are unable to escape and infect other cells," explains Enjuanes, a CSIC researcher at the CNB.

Advantages of intranasal administration

By eliminating several of the genes from the original virus that contributed to its virulence, the replicons generated by Professor Enjuanes' team are especially safe as vaccines . Furthermore, they express several viral proteins beyond the S protein (the SARS-CoV-2 spike protein), enabling the activation of multiple types of immune system defenses, including antibodies, T cells, and immunological memory. In preclinical mouse models, this prototype vaccine has proven to be very safe , highly effective, and capable of protecting against re -infection with the same variant.

This new system offers several advantages over intranasal administration . First, the replicon's ability to copy itself (self-amplification) within the cell, which would allow for a reduction in the required vaccine dose. It achieves a greater induction of the immune response by containing different viral antigens and can block infection in the nasal mucosa (sterilizing immunity).

Another aspect highlighted by the CSIC is that intranasal administration allows the vaccine to act directly on the respiratory mucosa , precisely the entry point for the virus, thereby generating a potent local immune response. This has the added advantage that, as it is a noninvasive and more convenient route of administration, it could facilitate its use in mass vaccination campaigns or in vulnerable populations, according to the report.

The replicons selected for their potential as vaccine prototypes have been tested both in vitro and in vivo in humanized mouse preclinical models . "Cell culture experiments allowed us to select those replicons that produce a high number of virus-like particles , with a low inflammatory response. With this selection of replicons, animal experiments were addressed," the researchers note.

"While a single dose provides 60% protection in mice, the use of double intranasal immunization achieves 100% protection against SARS-CoV-2 infection. Furthermore, the undetectable levels of virus in nasal and lung samples indicate that the immunization is sterilizing," explain Enjuanes and his colleagues, researchers Sonia Zúñiga and Isabel Sola .

The vaccine also induced robust T cell activation (CD4+, CD8+), neutralizing antibodies against virus variants, and immunological memory cells. No significant adverse effects, including weight loss and significant lung inflammation, were detected in the rodents.

This study included versions of the replicons against both the initial variants of the virus ( Wuhan ) and the XBB.1.5 variant currently used in commercial vaccines. The researchers observed that the efficacy of each replicon is preferentially specific to the variant causing the infection, so it would be necessary to adapt the sequence to the circulating variant at any given time. This update would be easily accomplished in two or three months, the authors explain.

A step towards more effective and versatile vaccines

One of the aspects highlighted by the team is the possible greater efficacy of this vaccine in older people , a group that tends to show weaker responses to conventional vaccines.

“The effectiveness of current vaccines among older adults is limited. The immune responses generated in this group after receiving current messenger RNA vaccines are typically weaker. In this regard, our RNA replicon-based vaccine offers several advantages : it produces several viral proteins that activate different types of defenses, it multiplies within cells, allowing for the use of lower doses, and it is administered through the nose, which helps generate defenses right at the point where the virus enters ,” the researchers note.

The CSIC's work represents a significant advance in the development of next-generation vaccines against COVID-19. "Its safe design , its ability to generate complete immunity , its potential usefulness in older people, and its flexibility to adapt to new variants make it a promising candidate for future vaccination campaigns," he emphasizes.