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With the current 2019 coronavirus pandemic (COVID-19) spreading to nearly every country in the world, lockdowns, social distancing and other non-pharmaceutical interventions (NPIs) have been almost the only effective measures against the spread of the causative pathogen, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
This has spurred the accelerated development of vaccines as a definitive way out of this global crisis.
While several vaccines have obtained emergency use authorization by several regulatory authorities in Europe, Asia and the UK, the continued and rapid emergence of new variants with mutants that confer partial resistance to vaccines poses a significant challenge to the objective of immunity at the population level.
A new study by researchers at Mahidol University in Bangkok, Thailand, reports a COVID-19 vaccine candidate called HexaPro in the production of neutralizing antibodies against the SARS-CoV-2 spike protein in an animal model. The team published its findings on the bioRxiv* pre-print server.
Entrance mediated by peaks
The novel coronavirus mediates entry into the host cell via its spike protein. This carries a receptor binding domain (RBD) that binds to the angiotensin converting enzyme 2 (ACE2) receptor on the host cell. This binding triggers a conformational change in the spike protein, which allows viral infiltration into the cell, so that active replication can begin.
The spike protein is also the dominant immunogen of this virus and has been the primary focus of most vaccine development efforts. To facilitate this, the prefusion conformation of the peak was stabilized by the introduction of two successive prolines (S-2P), at the level of the loop intervening between the central helix and repeated heptad 1 of this protein.
S-2P variants with a C-terminal trimerization domain have increased immunogenicity, and these have become standard in currently used vaccines from Moderna, Pfizer and Astra-Zeneca.
Spike subunit
This article discusses a COVID-19 vaccine candidate developed based on a recently reported proline stabilized advanced pre-fusion ectodomain subunit – HexaPro.
The researchers found that it induces a robust neutralizing antibody response in mice against SARS-CoV-2, and could be further developed as a second-generation coronavirus vaccine.
The subunit vaccine is based on the advanced ectodomain which has six substitutions with proline as well as a GSAS substitution at the furin cleavage site, in addition to the C-terminal fold on the trimerization domain.
Induction of neutralizing activity
The mice were inoculated intramuscularly with a prime-boost protocol. A microneutralization assay showed that the serum of mice immunized two weeks after the booster dose induced high titers of neutralizing antibodies. This level was maintained for at least eight weeks.
The HexaPro subunit spike vaccine candidate produced potent neutralizing responses. This spike protein ectodomain has four additional proline substitutions to further stabilize the prefusion conformation. This is in the S2 domain of the stabilized S-2P peak.
In this new variant of the pre-fusion peak, one third of the RBDs of the trimeric peak are in “high” or open conformation. As a result, two RBDs are exposed instead of the single RBD exposed in the S-2P peak. The increased stability has spurred the current exploration of HexaPro as a potential vaccine candidate against COVID-19.
The SARS-CoV-2 HexaPro recombinant spike protein. (A) Schematic representation of the pre-fusion stabilized SARS-CoV-2 HexaPro ectodomain showing the S1 and S2 subunits. Four additional proline substitutions from the S-2P construct are indicated by the red arrows shown below the construct. (B) The HexaPro protein expressed in HEK293T cells was purified and characterized by SDS-PAGE (left), Western blot using commercial anti-RBD (middle), and Western blot using pooled convalescent sera ( to the right).
The use of alum (aluminum hydroxide) in vaccines is associated with increased activity of dendritic cells and T cells, typical of inflammation. A recent phase 1 trial using alum with inactivated SARS-CoV-2 virus BBV152, and other clinical trials using subunit SARS-CoV-2 vaccines or inactivated SARS vaccines- CoV-2 with alum are also in progress.
In addition to the use of alum as an adjuvant, this article describes the use of a low priming dose and a high booster dose. This is supported by numerous studies in which this profile is known to induce a stronger immune response. An important study of interest is the randomized controlled trial of the approved Oxford-Astra-Zeneca vaccine.
Higher doses of an immunogenic antigen at the time of the priming dose may suppress recruitment of effector cells. Conversely, immune memory cells are induced by lower first-order doses. Thus, a low prime-high booster dose regimen appears to be more suitable for inducing a sustained anamnestic immune response.
What are the implications?
The current study shows that the HexaPro stabilized prefusion tip ectodomain is a very stable conformation. Its production is suitable for rapid and profitable production. It is also easily transported, overcoming logistical barriers.
Given the strong neutralizing response elicited in animals immunized by this subunit vaccine candidate, the researchers suggest this should be investigated further. For example, selected mutations should be introduced to induce effective immunization against different variants of SARS-CoV-2. Other vaccine platforms, such as mRNA, viral vector, and DNA vaccines, can also effectively use this antigen.
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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