A new approach to COVID-19 vaccine development

12 May 2021

A combined 2-in-1 vaccine strategy provides for simultaneous presentation of antigens on cell surfaces and on non-infectious virus-like particles.

The ongoing Covid-19 pandemic can only be brought under control with the aid of safe and effective vaccines. Using a combinational strategy, researchers led by Alexandru Hennrich and Karl-Klaus Conzelmann (Max von Pettenkofer Institute and Gene Center, LMU Munich), together with Christian Pfaller (Paul Ehrlich Institute, Langen) have now developed a novel vaccine candidate, which has proven to be safe and highly effective in an animal model.

The candidate vaccine consists of a self-replicating RNA or ‘replicon’, which is derived from the Vesicular Stomatitis Virus (VSV) and, in addition, carries part of the genetic information for the synthesis of the spike protein of SARS-CoV-2, which confers immunity to the coronavirus. Unlike the vaccines now in use the novel VSV replicon actually codes for only a short fragment of the spike protein (called the ‘minispike’), which consists of the receptor-binding domain (RBD) alone fused to a membrane anchor. Following synthesis of the RBD after uptake of the virus replicon into cells, the immunogen is presented on the cell surface and induces the generation of antibodies against SARS-CoV-2. This approach precludes the generation of ineffective or interfering – and hence potentially deleterious – antibodies by the immune system, says Conzelmann.

Importantly, the minispike protein also includes a membrane-anchor segment derived from a rhabdovirus. This enables the protein encoded by the VSV replicon to be assembled into what are called ‘virus-like particles’ (VLPs). These VLPs can be secreted from the cells in which they are synthesized, but are unable to infect other cells. As a result, the SARS-2 RBD is displayed both on the cell surface, and as an integral component of VLPs – a combination that markedly enhances the immune response against the minispike. Hence, the system consists of a conventional vector-driven vaccine and a VLP-based vaccine, and therefore represents an example of what immunologists call a 2-in-1 strategy. In animal experiments, the 2-in-1 vaccine induced the production of very high antigen titers. Furthermore, transgenic mice that are susceptible to infection by SARS-CoV-2 were protected from the pathogen after single-shot immunization with the vaccine.

The authors of the study regard their new VSV minispike approach as a possible alternative COVID-19 vaccine for use in immunocompromised individuals, and as a promising first step toward the development of vaccines against pathogens for which no effective immunity-inducing preparations are yet available.

PLOS Pathogens 2021

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