Intranasal COVID-19 vaccine developed from bacterial extracellular vesicle induces robust antibody response in preclinical trials

A team of US-based scientists recently developed a novel vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19). The vaccine is composed of extracellular vesicles of Salmonella typhimurium incorporated with the spike receptor-binding domain (RBD) of SARS-CoV-2. Upon intranasal administration in hamsters, the vaccine induces strong blood antibody titers and protects against severe COVID-19. The study is currently available on the bioRxiv* preprint server.

Background

In addition to non-pharmacological control measures, including mask-wearing, handwashing, and physical distancing, rapid and large-scale global vaccination programs are the key to prevent SARS-CoV-2 transmission and control the COVID-19 pandemic. Currently, various types of potential COVID-19 vaccines are rolling out globally, including mRNA-based (Pfizer/BioNTech and Moderna) and adenovirus vector-based (Oxford-AstraZeneca) vaccines that contain SARS-CoV-2 spike protein as immunogen. These vaccines have shown more than 85% efficacy in preventing SARS-CoV-2 infection in clinical trials and real-world pandemic situations. However, certain factors may negatively impact vaccine benefits, including manufacturing complexity, stability and storage, reaction speed, and lower efficacy against emerging viral variants.

In the current study, the scientists have developed a novel COVID-19 vaccine candidate based on bacterial extracellular vesicles decorated with SARS-CoV-2 spike RBD.

Vaccine design

Extracellular vesicles, also called outer membrane vesicles, of gram-negative bacteria, such as Salmonella typhimurium, are known to cause bacterial endotoxin-mediated induction of inflammatory and immune responses in host cells. Such immunostimulatory properties of extracellular vesicles have been utilized in the vaccine.

To avoid the potential risk of systemic toxicity, the scientists have prepared extracellular vesicles from an endotoxin-attenuated strain of Salmonella typhimurium. Moreover, they have used a specialized peptide sequence (SpyCatcher peptide) to attach SARS-CoV-2 spike RBD to the surface of the extracellular vesicle via a covalent amide bond. This covalent bond maintains the stability of the formulation under a wide range of pH, temperature, and buffer conditions. They have conducted a series of experiments, including Western blot, nanoparticle tracking analysis, and immunogold electron microscopy, to confirm the successful decoration of spike RBD on the surface of the extracellular vesicle.

Validation of vaccine efficacy

The scientists tested the vaccine in golden hamsters. The vaccine was administered intranasally at days 0, 14, and 28. Subsequently, the hamsters were challenged with live SARS-CoV-2 at day 44 post-immunization.

Regarding immune responses, high levels of IgG-specific anti-spike RBD antibodies were detected in the plasma of hamsters at day 42 post-vaccination. Specifically, the majority of hamsters developed detectable levels of anti-RBD antibodies by day 7 after the 1^st vaccine dose. The antibody titers reached peak values after the 1^st booster dose on day 14. However, no further induction in antibody level was observed after the 2^nd booster dose at day 28.

In the case of respiratory viruses like SARS-CoV-2, mucosal antibodies act as a first-line of dense. In this context, all vaccinated hamsters showed detectable levels of anti-spike RBD IgG antibodies in bronchoalveolar lavage samples 4 days after the viral challenge. In addition, IgM- and IgA-specific antibodies were detected in 62% and 75% of vaccinated hamsters, respectively.   

Regarding clinical consequences of SARS-CoV-2 infection, no significant reduction in body weight was observed in vaccinated hamsters by day 4 post-viral challenge. In contrast, unvaccinated hamsters showed a significant reduction in body weight at days 3 and 4 post-challenge.

Importantly, about 100 to a 1000-fold reduction in lung viral load was observed in vaccinated hamsters 4 days after viral challenge, as compared to that in unvaccinated hamsters. Regarding histopathologic changes in the lungs, vaccinated hamsters displayed fewer focal patches of inflammation, hemorrhagic areas, and alveolar edema at day 4 post-challenge. In contrast, unvaccinated hamsters exhibited multiple lesions and inflammatory patches in the lungs.  

Study significance

The study describes the development and validation of a bacterial extracellular vesicle-based vaccine candidate against COVID-19. The vaccine induces strong anti-SARS-CoV-2 antibody responses in the lung mucosa and plasma of hamsters. Moreover, the vaccine exhibits high efficacy in reducing clinical burdens related to SARS-CoV-2 infection.

The study also highlights the benefits of using bacterial extracellular vesicles as a vaccine platform. As mentioned by the scientists, the major advantage is that large amounts of vesicles can be rapidly and easily obtained from hypervesiculating bacteria like Salmonella typhimurium. Moreover, extracellular vesicles are highly stable even at room temperature and can be easily decorated with a wide variety of vaccine immunogens. Most importantly, because of self-immunostimulatory properties, extracellular vesicle-based vaccines do not require adjuvants.

*Important notice

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

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.