Antibodies targeting glycoprotein S (protein S) have been identified in SARS-CoV-2 seroconversion. They mainly target an immunodominant region of S: the Receptor Binding Domain (RBD). Many of these antibodies confer protection in vivo, but the magnitude of antibody responses to the S protein following natural infection varies considerably. For example, basal responses are generally maintained for months but may decline within weeks of infection, particularly in asymptomatic individuals. A vaccine approach that would induce sustained immunity capable of preventing infection and transmission of the virus would be a major asset in the fight against the pandemic.

The stability of native S-glycoprotein is limited, yet its stability is essential for the presentation of relevant epitopes in a vaccine. Researchers at IRIG used chemical cross-linking with formaldehyde, widely used in clinically approved vaccine formulations, to increase the stability of the protein S and thus preserve its native conformation for extended storage periods.
In collaboration with the François Jacob Institute of Biology, the University of Amsterdam and the Pasteur Institute, IRIG researchers then presented these S antigens in the form of lipid nanoparticles via liposomes. These offer a controllable degree of multivalence and stability as well as a prolonged circulation half-life in vivo. Preclinical studies with the protein S-loaded liposomes induced high antibody titers after two immunizations with potent neutralizing activity against the vaccine strain (alpha, beta and gamma variants). Although the predominant initial antibody response was directed against RBD, a third immunization significantly increased the production of antibodies directed against other regions of the S protein, encoded by sequences less prone to mutations. Immunization with the lipid nanoparticles led to complete protection against SARS-CoV-2 infection. In fact, the data indicate sterilizing immunity, because no viral replication could be detected during SARS CoV-2 infection of the vaccinated group compared to the unvaccinated control group. This protection is most likely correlated with the presence of significant antibody titers in the nasopharyngeal mucosa.

The generation of a vaccine candidate via lipid nanoparticles thus proves to be an effective approach, based on a classical and proven approach. In addition, the study provides a pathway to induce sterilizing immunity in correlation with a mucosal immune response that is desired to prevent the spread of the virus.