The ongoing coronavirus disease 2019 (COVID-19) pandemic has spurred intensive vaccine-related research. As yet, no targeted, safe and effective antivirals have been developed – and those which have been repurposed have had only limited effectiveness. Vaccines against the pandemic’s causative pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remain the most expedient way out.
A recent study released on the bioRxiv* preprint server reports the safety and high efficacy of an adjuvanted vaccine candidate against the virus and the complications of the disease.
The two earliest vaccines to be approved for emergency use were the Pfizer/BioNTech and the Moderna vaccine, both based on a messenger ribonucleic acid (mRNA) platform. The mRNA encodes the viral spike antigen, which is the target of most neutralizing activity.
Adenoviral vector-based vaccines have also been approved for use in many countries. These are also based on the spike protein, a trimeric protein bound to the surface of the viral membrane. This protein is metastable in the prefusion conformation, and undergoes conformational change when it binds to the host cell receptor, the angiotensin-converting enzyme 2 (ACE2), via its receptor-binding domain (RBD).
This mediates viral-cell membrane fusion, as well as syncytium formation between adjacent cells, causing the internalization of the virus, as well as the release of the virus to neighboring cells, and the subsequent spread of infection.
Anti-RBD antibodies neutralize spike-ACE2 binding by blocking the recognition of the ACE2 receptor by the spike antigen. The presence of multiple epitopes on the spike, even outside the RBD, has led to the use of the full-length spike rather than the RBD alone for vaccine development.
Designed for prefusion stability
The spike used in the current vaccine candidate contains designer mutations to inhibit the cleavage of the protein into its two subunits, a process that precedes spike-mediated membrane fusion, and also to stabilize the prefusion spike conformation. This is called the S-2P antigen and is the preferred antigen for multiple viral vaccines using the mRNA, lipid nanoparticle, or adenoviral vector platforms.
The current vaccine candidate, however, makes use of a soluble viral protein combined with an adjuvant for higher immunogenicity. This formulation is already found in several vaccines and is active against many age groups. The adjuvant is required to induce potent T and B cell immune responses.
The adjuvant used with the S-2P-based soluble protein antigen is AS03, which is highly immunogenic and increases the persistence of vaccine effects, widens the range of reactivity to include other variants, and reduces the dose of viral protein required in the vaccine.
AS03 has been used in influenza vaccines in Europe, of which about 90 million doses have been given to patients.
The current study shows that this adjuvanted protein-based vaccine induces antibody responses high enough to ensure protection against infection and to achieve viral clearance from the lungs.
Immunogenicity of soluble trimeric spike antigens with AS03
The study showed that the prefusion transmembrane-deleted spike, or preS dTM, adjuvanted with AS03, induced binding and neutralizing immunoglobins at high levels, as well as specific IgA and IgG antibodies. This effect was dependent on the presence of AS03 in the formulation.
The AS03-induced antibodies were found to bind broadly across multiple Fc receptors and to mediate Fc-dependent phagocytosis, complement activation and similar effector functions. The magnitude of these functions appeared comparable across all Fc receptors.
These data establish the critical role of the AS03 adjuvant for improving the magnitude and quality of antibody responses.”
When used to immunize non-human primates, this formulation induced binding antibodies at titers similar to those in convalescent serum from two reference cohorts after the first dose and markedly higher titers after the booster dose. The use of 4 and 12 µg dosages failed to cause any change in the magnitude of the antibody response.
The induced antibodies are bound to the S1 spike subunit, especially the RBD and the N-terminal domain (NTD). Not only did these show increased avidity of binding, but they competed for binding to the RBD with ACE2 at a hundred-fold higher level.
Post-booster dose, almost all immunized animals showed high neutralizing titers, and functional assays showed potent neutralization of live virus at ten-fold higher levels than with convalescent serum.
However, the neutralizing activity dropped two-fold, and five- to ten-fold against the UK and South African variants of the virus.
The vaccine candidate also elicited spike-specific memory CD4 T cells, including T helper 1 (Th1) producing interleukin -2 (IL-2) and tumor necrosis factor (TNF). Only 7% of cells produced Th2 cytokines. CD8 T cells were almost undetectable.
Protection against viral challenge
The vaccine candidate also protected NHPs from infection even at high doses of the virus given intratracheally and intranasally, at three weeks after the second dose. Subgenomic RNA (sgRNA), which indicates replicating virus, in bronchoalveolar lavage fluid (BALF), was found to be lower in immunized animals following viral challenge, from the second day onwards, in a dose-dependent fashion. By day 7 post-vaccination, almost 60% and 6% of control and immunized animals showed sgRNA in BALF, indicating that the lower airway was protected.
Upper airway protection was assessed by nasal swab sgRNA measurement. This showed the same results. Thus, “AS03-adjuvanted preS dTM provided significant protection in the upper and lower airways from this robust SARS-CoV-2 challenge.”
Lung tissue in challenged animals showed limited and undetectable antigens in NHPs that received low- and high-dose immunization, respectively. At week 5, following the second dose, spike-specific IL-2, IFNg, and IL-13 memory responses were higher in the vaccinated groups. A strong Th1 response was observed in the BALF but not in the peripheral blood mononuclear cells (PBMCs).
What are the implications?
This suggests that the vaccine-induced viral control successfully even before the generation of a primary T cell response in the lungs or the blood. In fact, SARS-CoV-2 challenge causes a temporary rise in IgG locally, which is seen at an earlier time point following vaccination.
The vaccine-elicited antibodies also conferred passive protection against subsequent viral challenge in a dose-dependent fashion, indicating that “the AS03-adjuvanted preS dTM vaccine-elicited IgG sufficient to mediate protection in vivo against SARS-CoV-2 infection.”
The study demonstrates the powerful antibody response induced by this novel formulation, able to protect both the upper and the lower airways following viral challenge.
These data support the clinical development of the AS03-adjuvanted preS dTM vaccine for limiting SARS-CoV-2 infection and protecting against COVID-19 morbidity and mortality.”
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.