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.
The outbreak of a novel coronavirus (CoV) causing severe acute respiratory syndrome (SARS) was initially identified in China in late 2019 and rapidly developed into a global pandemic with devastating health and economic consequences1. Driven by this, concerted effort by hundreds of laboratories across the world has led to the most rapid vaccine development in history, with clinical trials of promising candidates completed within a few months of the virus genome being reported2,3. Surprisingly, established vaccine technologies such as those based on inactivated/attenuated virions (entire virus particles) or on viral protein fragments, which have traditionally led the way in terms of clinical presence, market share and regulatory approval, have been clearly outplayed in both speed and immunoprotective efficacy by highly innovative technologies with no prior approved clinical use4. Even more remarkable is that most of these vaccine candidates rely on either synthetic or naturally occurring nanoscale vector systems (Table 1), with almost all of the candidates falling within the nanoscale size range (Fig. 1).
The current scale of administration and therefore exposure to non-viral or viral nanoparticles constitutes an unprecedented phenomenon of historic proportions and implications. The immediate reaction, even by some members of the scientific community, has been to acclaim nanoscience and nanomedicine as ‘saviours’ of humankind. However, what should be emphasized is that the successful implementation and mass rollouts of nanoscale vaccines we are now seeing are the result of years of research and product optimization that should certainly be celebrated, with investment in the area maintained. On the other hand, we believe that shallow glorification of nanomedicine should be avoided, and that consideration, caution and retrospective thinking should prevail, as we move forward epidemiologically in managing the pandemic.
Engineering nanoscale vaccines
To understand why ‘nano’ worked in this case, let us look at the nanoscale nature of the vector technologies that make the COVID-19 vaccines efficacious. For each of the three vaccine types currently being mass-administered to human populations (the non-viral mRNA–lipid nanoscale complex vaccines from Pfizer/BioNTech and Moderna; the genetically engineered viral nanoscale vaccines from AstraZeneca/Oxford, Janssen/J&J, Gamaleya and CanSino; and the conventional vaccines based on inactivated coronavirus from Sinopharm and Sinovac), we highlight the main lessons learnt from their extraordinarily rapid deployment and the challenges that remain (Boxes 1–3).
The case of mRNA–LNP complexes
The first COVID-19 vaccines to reach clinical testing and subsequent approval (initially by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom) were the non-viral complexes based on lipid nanoparticle (LNP)-encapsulated mRNA encoding some form of the SARS-CoV-2 spike protein (Moderna) or its receptor binding domain (Pfizer/BioNTech)2,3,5. Despite no mRNA-based vaccines being previously approved for any pathology, the high efficacy (90–95%) against SARS-CoV-2 infection in Phase III clinical trials led the MHRA, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve the vaccines for emergency use in late 20206,7. While Pfizer/BioNTech and Moderna lead the way on this front, several alternative mRNA or self-replicating RNA-based vaccines are also in the clinical pipeline (Table 1). The mRNA itself is responsible for producing the active immunogen; and the design of this sequence to best mimic native antigen conformation, combined with advancements in nucleic acid engineering to maximize translation8, is fundamental to the success of this approach. However, without a nanoscale transport system to enable protected translocation of the mRNA across the plasma membrane and into the cytosol, it is doubtful whether enough mRNA molecules would provide the high levels of expression needed for immunogenic efficacy.
Both Pfizer/BioNTech and Moderna encapsulate their mRNA cargo inside an LNP. The use of LNPs to deliver nucleic acids intracellularly is not a new technology. Many investigators and commercial entities (mainly active in the gene therapy field) have explored preclinical and clinical applications of this technology, with evidence of clinical success, culminating in the recent approval of Onpattro9,10. Decades of research, including cellular mechanistic studies alongside advances in lipid synthesis, biochemistry and liposome science, have been undertaken to engineer LNPs from their beginnings as delivery systems for small molecules and proteins, through a lot of rational design optimization needed for effective intracellular transport of larger nucleic acids (such as mRNA).
Most of the mRNA vaccines against COVID-19 have been based on swift adaptation of existing nanoscale complexes for small interfering RNA (siRNA) therapeutics or mRNA vaccines for other diseases9,10. These were originally designed for intravenous administration, and aspects of their formulations have largely been carried over11,12. For example, the inclusion of polyethylene glycol (PEG), which has been well studied in liposomal drug delivery, with the ability to colloidally stabilize nanoparticles and provide a hydrophilic steric layer, plays a pharmacological role in prolonging blood circulation following systemic administration13,14. Although PEG can offer enhanced stability of the nanoparticle systems, the instability of the mRNA cargo in the case of the Pfizer/BioNTech and Moderna COVID vaccines means that these still have to be stored and transported at ultra-low temperatures. There are various socioeconomic factors to be considered, and there are difficulties in transporting and storing non-thermostable vaccine formulations, especially for low-income countries15. Engineering the nanoscale transport systems further to improve the overall thermostability of the complex, while also optimizing for the appropriate route of administration, may improve effectiveness or longevity of immunoprotection, aid the usage of these highly efficacious vaccines in the developing world, and allow the design and clinical application of vaccine platforms against more complex pathophysiological conditions, such as cancer or neurodegeneration.
The case of adenoviruses
The non-viral mRNA complexes presented above were developed more rapidly and with higher reported efficacies than genetically modified viral nanoparticle-based vaccines. This is remarkable, as it is the first time since the late 1980s (when research on therapeutic genetic technologies began) that a non-viral nucleic acid vector system has been equivalent to, if not more efficacious than viral vectors for any clinical application.
The only approved viral vector COVID-19 vaccines currently in mass vaccination roll-outs are based on adenovirus. Adenoviruses are naturally occurring nanoscale objects (perfectly shaped, regular icosahedron nanoparticles that range in diameter between 90 and 100 nm) with a long and tumultuous history of successes and failures in a wide variety of gene therapy applications16. The recognition of adenoviruses as nanoparticles of biological nature has allowed their surface and structural engineering at the nanoscale, leading to re-designed vectors with versatile capabilities17. All of the currently authorized COVID-19 adenovirus-based vaccines are based on a typical adenoviral nanoparticle, genetically modified to replace their key codons for replication (E1/E3) with DNA sequences encoding for a version of the SARS-CoV-2 spike protein (or its receptor binding domain). However, key differences exist in their design. The Oxford/AstraZeneca vaccine (ChAdOx1 nCoV-19) comprises a novel chimp adenovirus (ChAd) to overcome potential pre-existing anti-vector immunity18, whereas the Gamaleya Research Institute vaccine (Sputnik-V) uses a heterologous prime-boost approach where the first dose is provided in a human type-26 adenovirus (Ad26), followed by a traditional human type-5 (Ad5) second dose to overcome any anti-vector immunity generated by the first dose19. The only previous case of an approved adenovirus-based vaccine is the Ad26-based Ebola vaccine approved in 2019, which of course did not have the current widespread use20.
Most of the vaccines developed against COVID-19 require a two-dose administration regimen. There are various potential complications of this, including the higher risk of anaphylactic or adverse reactions during one of the injections, and obviously the cost and inconvenience to health systems. There seems to be a tendency to overcome most of these challenges in the adenovirus vector vaccine space by approvals of single-dose vaccinations. Janssen/J&J obtained authorization for emergency use of their vaccine as a single administration across the United States, United Kingdom and European Union, reporting an efficacy of around 60–85% prevention of moderate to severe disease21. Similarly, the CanSino adenovirus-based vaccine aims toward a single-shot approach, with their Phase II trial reporting robust immunogenicity22. The Oxford/AstraZeneca vaccine also has demonstrated single-dose effectiveness23. There remain unanswered questions as to why the ‘single-shot’ approach was not preferred in the first place, whether consecutive doses offer further significant levels of protection, and whether the ‘two-shot’ approach provides longer-lasting immunity24. From the perspective of viral nanoparticle exposure, the scale of human exposure to adenovirus particles undertaken at the moment is unprecedented, so any nanotoxicological and immunotoxicological limitations will surely be unravelled. One such effect is the rare blood-clotting events reported within days from the administration of the authorized adenoviral vaccines (both AstraZeneca and Janssen/J&J)25,26. There is a need for mechanistic immunotoxicology to decipher the reasons behind such adverse effects.
Currently, at least five of the adenovirus-based vaccines developed against COVID-19 are using the Ad5 serotype as the DNA carrier (Table 1). Ad5 is ubiquitous in nature and infects humans frequently, leading to a very high prevalence of anti-Ad5 antibodies in populations worldwide, which in turn may jeopardize the efficacy of the vaccination27. However, even with the use of more novel serotypes with substantially less initial seroprevalence (Ad26, ChAd), there is the open question of whether the serotype-specific anti-adenovirus immune response generated by the first dose (or series of doses) will severely limit the effectiveness of a booster shot, or those designed against new vaccine-resistant variants, which may be required in the future. Nanoscience can play an important role in addressing this challenge by nanoscale engineering of the adenovirus surface capsid, using lipid or polymer molecular self-assembly and conjugation strategies28,29,30,31,32.
The case of protein subunit and inactivated coronaviruses
The clinical success and approval of both mRNA–LNP and adenovirus-based approaches demonstrate that synthetic, rationally designed or naturally occurring genetically engineered nanoparticle vector systems can work effectively and play a critical role in resolving the COVID pandemic. Of note, the peculiarity we have witnessed of nano-enabled approaches being first to market is scientifically supported by a number of failures in the conventional vaccine landscape (see abandoned trials in Table 1)33,34,35. Despite varying reports of efficacy (ranging from 50% to 83%), several more conventional vaccine technologies including inactivated SARS-CoV-2 and protein subunit approaches have now seen emergency authorization in at least one country (Table 1), with many others progressing through clinical development. As time progresses, and results from Phase III trials are released, clarity will emerge over whether these conventional approaches match the efficacy of the nanoscale mRNA–LNP and viral vector strategies. It will be particularly important to obtain credible and transparent data from the mass-vaccination programmes undertaken with these vaccines in different regions of China.
Nanoscale engineering and creativity is abundant in this vaccine category too. Conventional protein subunit vaccines have been modifed, for instance by generating virus-like protein complexes to enable better antigen-presenting-cell uptake and antigenicity. Novavax exploits this, with its recombinant nanoparticle vaccine (NVX-CoV2373), consisting of a spike protein complex with Matrix-M1 adjuvant, demonstrating high efficacy (up to 89%) against a number of different SARS-CoV-2 variants36,37. This indicates that further refinement and modification of these conventional protein-based vaccine approaches could provide competitive strategies that also offer cost and manufacturing advantages over mRNA–LNP or viral vector systems.
Although mainly nanotechnology-enabled COVID-19 vaccines are currently approved for emergency use, it will be interesting to monitor, as more conventional approaches gain approval, whether the reduced cost, simplicity in manufacturing and logistical benefits will eventually lead these conventional vaccine types to take over clinical use worldwide, particularly if a repeat booster vaccination (annual or more frequent) is required to maintain immunity against spreading mutations38.
Transient success or fruits of a mature field
During the past year, and following the call to arms for nanoscience research at the beginning of the pandemic in Europe39, advances in nanotechnology and nanomedicine have had an indisputably important impact. This is quite redemptive for a field that has recently gone through a phase of self-doubt and subsequent maturity, albeit mainly, and perhaps too narrowly, in relation to clinical translation of nanotechnologies in oncology40,41,42. Given the successful development, upscale manufacturing and launch in mass-vaccination programmes around the world of nanoscale lipid-based mRNA (non-viral) and nanosized adenovirus-based (viral) vaccines, there is the danger of triumphalism for nanomedicine. This is inappropriate and risks diminishing credibility for this thriving field.
Reasons for nanoscience innovation to win over conventional strategies
Both the non-viral and viral nanoscale vaccine vectors currently being injected into millions of people are technologies that previously had almost no (or, at best, ‘niche’) clinical presence. In that sense, they are innovative. But both vector platforms have undertaken at least a 25-year-long development pathway towards clinical translation in many different therapeutic approaches and disease indications. Both technologies have already gone through multiple cycles of successes, failures, near-misses and false starts, in the hands of multiple academic, clinical and industrial parties. We believe that this is the true reason behind their successful deployment with such speed and potency. The level of accumulated knowledge and creative work behind different aspects of those systems (chemically, molecularly, biologically and pharmacologically) is vast and did not start last year. It would certainly be naïve to think that lipid-based and adenovirus-based vector technology platforms have been an invention of the past few months.
Nanomedicine success could be a transient result of pandemic-driven opportunism
It is in the common interest that effective and safe COVID-19 vaccines should be rolled out in mass-population vaccination campaigns. The fact that established vaccine technologies take longer to develop and are much less effective in preventing severe disease and shielding against infection4,33 has offered the nanoscale lipid-based and adenovirus-based vaccine vectors an opportunity in terms of science and technology, but also in terms of market share. It is debatable whether these nanoscale vaccines will continue to be used in population-wide vaccination programmes even after more conventional, established and cheaper vaccines (for example, those based on adjuvanted protein fragments) have been launched. The biological complexity and evolution of the prevalent coronavirus strains themselves will also determine the effectiveness and ease of engineering adaptability needed by future vaccines. There are still a few unknowns that could determine their longer-term use against COVID-19 in the future, such as (1) the duration of protection against infection; (2) the ease and flexibility of incorporating new sequences against new coronavirus mutants; (3) the simplification of manufacturing processes and logistics in handling (maintenance, storage, stability); and (4) cost.
Traditional vaccines could achieve all of the above with reasonable protection and at a fraction of the cost, provided they are efficacious against and easy to adapt to new CoV variants. The innovative nanoscale vaccines currently used (primarily in the developed, western hemisphere) can result in overall economic benefits, provided they allow lifting of severe restrictions. However, it is hard to imagine how to overcome the high cost of manufacturing, maintenance and transport of thermolabile molecules (RNA, lipids) to vaccinate the developing world en masse. Considering that mRNA–LNP vaccines have been under clinical development (but not authorized for use before the pandemic) against various viruses including influenza viruses, rabies and Zika virus8, the safety and efficacy profile observed during the COVID-19 pandemic will certainly pave the way for these prophylactic vaccines as well. Also, it must be stressed that both non-viral and viral nanoscale vector technologies were originally developed with the intention to be used against more biologically complex pathological conditions and disease states, such as cancer. It will not be surprising if the mRNA–LNP (and to a less extent the adenovirus) vector systems return to re-focus on the development of vaccines for more complex (for example, cancer, neurological diseases) and rare diseases after the pandemic subsides.
Transformative impact on approval and acceptance of new nanoscale technologies for medicine
Humankind is not familiar with using nanoscale objects so widely. That may explain the degree of unease from many in accepting multiple injections of nanoparticle-based vectors. It can also lead to extreme views and conspiracy theories (for example, wireless nanorobotic chips contained in vaccines) that some circles wish to propagate to serve their own political agendas. That is why caution, consideration, understanding and accurate communication of the scientific and clinical facts generated from such an unprecedented and intended exposure to nanoparticles to the public are needed. Provided that short- and long-term safety is not compromised, the extent of nanoscale vaccine deployment that we are witnessing will surely have a marked impact on how regulators, ethics review committees and investors view nanoscience and nanotechnology used in medicine.
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T.K. and K.K. acknowledge financial support from the UK Research & Innovation Engineering and Physical Sciences Research Council International Centre-to-Centre grant (EP/S030719/1). A.Y. thanks the Scientific and Technological Research Council of Turkey (TUBITAK, 18AG020) and the Turkish Academy of Sciences (TUBA, GEBP 2018) for financial support.
The authors declare no competing interests.
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Kisby, T., Yilmazer, A. & Kostarelos, K. Reasons for success and lessons learnt from nanoscale vaccines against COVID-19. Nat. Nanotechnol. 16, 843–850 (2021). https://doi.org/10.1038/s41565-021-00946-9