Reasons for Success and Lessons Learnt from Nanoscale Vaccines Against COVID-19
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comment Reasons for success and lessons learnt from nanoscale vaccines against COVID-19 Almost all currently used vaccines against COVID-19 consist of either non-viral or viral nanoparticles. Here we attempt to understand the reasons behind the success of such advanced nanoscale vaccine technologies compared with clinically established conventional vaccines, and the lessons to be learnt from this potentially transformative development in the adoption and acceptance of nanotechnology for medicine. Thomas Kisby, Açelya Yilmazer and Kostas Kostarelos he outbreak of a novel coronavirus vaccine technologies such as those almost all of the candidates falling within the (CoV) causing severe acute based on inactivated/attenuated virions nanoscale size range (Fig. 1). Trespiratory syndrome (SARS) was (entire virus particles) or on viral protein The current scale of administration initially identified in China in late 2019 and fragments, which have traditionally led and therefore exposure to non-viral or rapidly developed into a global pandemic the way in terms of clinical presence, viral nanoparticles constitutes an with devastating health and economic market share and regulatory approval, unprecedented phenomenon of historic consequences1. Driven by this, concerted have been clearly outplayed in both speed proportions and implications. The effort by hundreds of laboratories across and immunoprotective efficacy by highly immediate reaction, even by some members the world has led to the most rapid vaccine innovative technologies with no prior of the scientific community, has been to development in history, with clinical approved clinical use4. Even more remarkable acclaim nanoscience and nanomedicine trials of promising candidates completed is that most of these vaccine candidates rely as ‘saviours’ of humankind. However, within a few months of the virus genome on either synthetic or naturally occurring what should be emphasized is that the being reported2,3. Surprisingly, established nanoscale vector systems (Table 1), with successful implementation and mass Lipid nanoparticle: mRNA Inactivated SARS-CoV-2 Protein subunit Anhui Zhifei/CAMS Sinopharm Sanofi /GSK PEGylated lipid Sinovac Pfizer/BioNTech Bharat Biotech Instituto Finlay Ionizable de Vacunas Moderna cationic lipid Institute of Medical CIGB PLA Academy of Biology/CAMS Cholesterol West China Hospital Military Science Kazakhstan Research Institute /Sichuan University CureVac Beijing Minhai Biotechnology <20 nm Phosphatidylcholine Nanogen Valneva Pharmaceutical Erciyes University Biotechnology 70–100 nm 80–160 nm 1 nm 100 nm 1 µm Adenoviral vector Protein complex ChimpAd Oxford/AstraZeneca Janssen Pharmaceuticals/J&J Ad5 Gamaleya Research Institute CanSino Biologics Novavax Ad26 30–40 nm 80–120 nm Fig. 1 | Nanoscale COVID-19 vaccines and institutions. The figure shows the nanoscale COVID-19 vaccines authorized for emergency clinical use or in Phase III active trials (up to July 2021) and the institutions that have developed and/or market them. NATURE NANOTECHNOLOGY | VOL 16 | AUGUST 2021 | 843–852 | www.nature.com/naturenanotechnology 843 comment Most of the mRNA vaccines against Box 1 | Lessons learnt and challenges remaining for mRNA–LNP vaccines. COVID-19 have been based on swift adaptation of existing nanoscale complexes L essons learnt Challenges remaining for small interfering RNA (siRNA) • Tolerable and efficacious mRNA • Thermal instability of mRNA cargo and associated therapeutics or mRNA vaccines for delivery system based on optimized logistical issues with maintenance and distribution other diseases9,10. These were originally lipid formulations derived from • Further optimization of the nanoscale delivery platform designed for intravenous administration, decades of liposome research is required, to be most appropriate for the site(s) of and aspects of their formulations have • Robust effectiveness of mRNA-LNP administration; to produce target-specific immuno- largely been carried over11,12. For example, vaccine systems activation; and to prolong the duration of the effect the inclusion of polyethylene glycol • Versatility of the mRNA vaccination • Achieving a ‘one-shot’ approach (PEG), which has been well studied in platform with fairly ‘universal’ LNP Cost is a roadblock for low- to middle-income countries, • liposomal drug delivery, with the ability delivery systems and leads to market competition with similarly effective to colloidally stabilize nanoparticles and but cheaper alternatives provide a hydrophilic steric layer, plays • Unclear longevity and type of immunoprotection offered a pharmacological role in prolonging • Hypersensitivity reactions blood circulation following systemic administration13,14. Although PEG can offer enhanced stability of the nanoparticle systems, the instability of the mRNA rollouts of nanoscale vaccines we are now infection in Phase III clinical trials led cargo in the case of the Pfizer/BioNTech seeing are the result of years of research the MHRA, the US Food and Drug and Moderna COVID vaccines means and product optimization that should Administration (FDA) and the European that these still have to be stored and certainly be celebrated, with investment in Medicines Agency (EMA) to approve the transported at ultra-low temperatures. the area maintained. On the other hand, vaccines for emergency use in late 20206,7. There are various socioeconomic factors to we believe that shallow glorification of While Pfizer/BioNTech and Moderna lead be considered, and there are difficulties in nanomedicine should be avoided, and that the way on this front, several alternative transporting and storing non-thermostable consideration, caution and retrospective mRNA or self-replicating RNA-based vaccine formulations, especially for thinking should prevail, as we move vaccines are also in the clinical pipeline low-income countries15. Engineering the forward epidemiologically in managing (Table 1). The mRNA itself is responsible nanoscale transport systems further to the pandemic. for producing the active immunogen; and improve the overall thermostability of the design of this sequence to best mimic the complex, while also optimizing for Engineering nanoscale vaccines native antigen conformation, combined the appropriate route of administration, To understand why ‘nano’ worked in this with advancements in nucleic acid may improve effectiveness or longevity case, let us look at the nanoscale nature engineering to maximize translation8, of immunoprotection, aid the usage of of the vector technologies that make the is fundamental to the success of this these highly efficacious vaccines in the COVID-19 vaccines efficacious. For each approach. However, without a nanoscale developing world, and allow the design and of the three vaccine types currently being transport system to enable protected clinical application of vaccine platforms mass-administered to human populations translocation of the mRNA across the against more complex pathophysiological (the non-viral mRNA–lipid nanoscale plasma membrane and into the cytosol, conditions, such as cancer or complex vaccines from Pfizer/BioNTech it is doubtful whether enough mRNA neurodegeneration. and Moderna; the genetically engineered molecules would provide the high viral nanoscale vaccines from AstraZeneca/ levels of expression needed for The case of adenoviruses. The non-viral Oxford, Janssen/J&J, Gamaleya and immunogenic efficacy. mRNA complexes presented above CanSino; and the conventional vaccines Both Pfizer/BioNTech and Moderna were developed more rapidly and with based on inactivated coronavirus from encapsulate their mRNA cargo inside higher reported efficacies than genetically Sinopharm and Sinovac), we highlight an LNP. The use of LNPs to deliver modified viral nanoparticle-based the main lessons learnt from their nucleic acids intracellularly is not a new vaccines. This is remarkable, as it is the first extraordinarily rapid deployment and the technology. Many investigators and time since the late 1980s (when research challenges that remain (Boxes 1–3). commercial entities (mainly active in on therapeutic genetic technologies the gene therapy field) have explored began) that a non-viral nucleic acid vector The case of mRNA–LNP complexes. preclinical and clinical applications of system has been equivalent to, if not The first COVID-19 vaccines to reach this technology, with evidence of more efficacious than viral vectors for clinical testing and subsequent approval clinical success, culminating in the any clinical application. (initially by the Medicines and Healthcare recent approval of Onpattro9,10. Decades The only approved viral vector Products Regulatory Agency (MHRA) in of research, including cellular mechanistic COVID-19 vaccines currently in mass the United Kingdom) were the non-viral studies alongside advances in lipid vaccination roll-outs are based on complexes based on lipid nanoparticle synthesis, biochemistry and liposome adenovirus. Adenoviruses are naturally (LNP)-encapsulated mRNA encoding science, have been undertaken to occurring nanoscale objects (perfectly some form of the SARS-CoV-2 spike engineer LNPs from their beginnings shaped, regular icosahedron nanoparticles protein (Moderna) or its receptor binding as delivery systems for small molecules that range in diameter between 90 and domain (Pfizer/BioNTech)2,3,5. Despite no and proteins, through a lot of rational 100 nm) with a long and tumultuous mRNA-based vaccines being previously design optimization needed for effective