In a paper published in Frontiers in Immunology in February 2023, researchers review the challenges associated with the development of virus-like particle (VLP) -based vaccines. With “only a few VLP-based vaccines have been commercialised”, and others “struggling” with “technical difficulties”, the article examines the reasons for this.  


The authors acknowledge the variety of vaccine platforms that are currently being pursued to tackle viral infectious diseases. Of these, VLPs are “considered real, present, licensed, and successful vaccines” due to their “non-infectious nature, structural similarity with viruses, and high immunogenicity”. This strong immunogenicity is thanks to the presentation of “repetitive antigenic epitopes to the immune system in more authentic confirmation”.  

VLPs are “non-infectious multiprotein structures” that contribute to “safe vaccine candidates” because they “lack the disease-causing viral genome”. Furthermore, they elicit a protective response at “lower doses”, reducing development and production costs. Clearly VLPs offer potential, but what are the challenges they present? 

Challenges associated with VLPs 

The first challenge that the paper identifies is linked to the “transduction related parameters”. The cell concentration at infection (CCI), multiplicity of infection (MOI), and time of harvest (TOH) in the baculovirus system “strongly influence protein expression” and therefore VLP assembly. The ideal time of harvest is 72-120 hours post-infection, and outside this period “various parameters can hinder productivity”. Furthermore, incomplete VLP released into the medium alongside target mature VLP can “hinder the downstream processing of VLP”.  

“The development of novel techniques for process optimisation is required.”  

Another challenge that VLPs present is assembly. The nature of stabilising contact can influence the VLP assembly route. Additionally, the “assembly and disassembly of VLPs may also depend on the ionic or reducing conditions in which they are assembled”.  

For “superior assembly effects”, cell-free or in vitro assembly requires control of variables like “temperature, pH, and specific assembly solution”. 

“When optimal conditions are not available, VLP destruction increases considerably.”  

The study recommends further investigation into optimisation for appropriate assembly. Once this has been achieved, additional challenges arise. One such challenge is in “maintaining stability”. VLPs can “become very unstable and tend to phase separately in solution”. The stability of VLPs is “essential” for the production of viable antigens for vaccine candidates.  

For example, the storage stability in “real-time, accelerated, and stress conditions” must be considered. Unfortunately, this is hard to define because a “conceptualised matrix is not available for VLPs owing to their non-linear nature in response to thermal and other external factors”

What next? 

With so many challenges identified in the paper, it is evident that the development of VLP-based vaccines is a strenuous, yet delicate, task. The authors encourage the overcoming of these “hurdles” to enhance commercialisation.  

“The financial viability of biopharmaceutical companies is the main hurdle in this process and needs to be addressed”.  

In particular, they emphasise the need to focus on lower and middle-income countries, as always, in the development and scaling-up of VLP-based vaccine candidates. What developments can we expect to see on this front, and are there challenges that the paper omits? How can these be overcome?  

For more on vaccine technologies join us at the World Vaccine Congress in Washington this April.