Second-generation COVID-19 vaccines – where are they positioned in the global vaccine landscape?

Since the outbreak of the COVID-19 pandemic, a major global effort has been put into accelerating the development of vaccines to limit the spread of the disease and prevent future outbreaks.

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Our journey began in February 2020, when we secured funding to develop a COVID-19 vaccine based on a modular Tag/Catcher-based capsid virus-like particle (cVLP) platform. The task was to design and produce the vaccine, demonstrate proof-of-concept in animal models, develop large-scale and GMP compatible production processes, perform toxicological studies, obtain regulatory approval and begin clinical trials to test the vaccine's safety and immunogenicity in humans – all in 12 months. This took an extraordinary effort from our small team, especially as the time-line did not allow for traditional step-by-step optimization. Thus, the small-scale vaccine production for the animal studies had to be directly scalable to GMP production.

The starting point for the development was our cVLPs platform for display of antigens, which had shown to significantly improve the immunogenicity of a variety of antigens [1]. The technology enables any antigen to be presented in a virus-like structural context (Figure 1).

Figure 1. Structural illustration of the RBD-CLP vaccine, based on the SARS-CoV-2 RBD, Tag/Catcher, and AP205 CLP structures. The Tag is shown in red, Catcher in green, RBD in grey with the amino acids residues involved in ACE2 binding interface shown as red spheres.

However, while some proteins are easily coupled to cVLP, others cause massive aggregation. Likewise, we had learned that the immunogenicity of different antigens is not equally boosted by the cVLP-display. On that basis, we started designing antigens based on the SARS-CoV-2 spike protein, with the ambition to fulfill the requirements to elicit a long-lived neutralizing antibody response. In the first months, many different antigen designs were tested and immunization studies were initiated for selected lead candidates, based on the receptor-binding domain (RBD). These initial studies showed that extensive optimization was needed to enable cVLP-display of the RBD antigen, especially considering the need for stability of the vaccine for long-term storage at practical temperatures. A combination of antigen design and buffer optimization finally resulted in a product showing stability for 6 month at -20oC and short-term stability at ambient temperature.

Our studies also confirmed the low intrinsic immunogenicity of the soluble RBD antigen that was strongly boosted by the cVLP display. To this end, a recent review sought to compare the immunogenicity of multiple different COVID-19 vaccine candidates [2]. When plotting our data into this comparative scheme (i.e. comparing in vitro virus neutralization) our vaccine emerges as a top candidate among the included COVID-19 vaccine. This emphasizes the importance of choosing an optimal vaccine vehicle for delivering the RBD antigen and demonstrates a major effect of displaying the antigen in a multivalent, high-density manner.

A fundamental challenge for current vaccines concerns their ability to induce durable immune responses, and among currently marketed sub-unit vaccines, only the cVLP-based HPV vaccines seem to fully achieve this goal. We believe the cVLP-based platforms hold great potential due to their structural resemblance with the HPV vaccines. Importantly, the first COVID-19 vaccines have recently been approved, showing promising efficacy. However, we do not yet know the longevity of the protection. Should these vaccines eventually prove incapable of inducing long-term protection, the cost of maintaining herd immunity would increase enormously due to the requirement for multiple booster vaccinations. Therefore, a strong rationale exists for continuing the development of next-generation COVID-19 vaccines with improved immunogenicity and stability. However, we must consider how these 2nd generation vaccines will perform in patients already vaccinated with a 1st generation COVID-19 vaccine.

  1. Thrane, S.; Janitzek, C.M.; Matondo, S.; Resende, M.; Gustavsson, T.; de Jongh, W.A.; Clemmensen, S.; Roeffen, W.; van de Vegte-Bolmer, M.; van Gemert, G.J.; et al. Bacterial superglue enables easy development of efficient virus-like particle based vaccines. J. Nanobiotechnology 2016, 14, 30.
  2. Moore, J.P.; Klasse, P.J. SARS-CoV-2 vaccines: ‘Warp Speed’ needs mind melds not warped minds. J. Virol. 2020.

Adam F. Sander

Associate Professor, AdaptVac