By Maria João Cruz, PhD, Research Analyst, Centre for Health Solutions


In early May, we published a blog about the race for a COVID-19 vaccine.1 At the time, biotech and biopharma companies together with research organisations and academia had commenced the development of some 110 potential vaccines against SARS-CoV-2. Notable features of the race include the unprecedented acceleration in the pace of R&D and the significant scale of collaboration and cooperation between stakeholders across multiple geographies.2 By the end of August, there are 203 vaccine candidates under development. Six have already reached Phase III or II/III clinical trials, the last stage of clinical development before vaccines can obtain regulatory approval (see Figure 1).3,4 This was achieved in only few months, rather than the years it would normally take.5 Importantly, the COVID-19 vaccine developers are using a variety of technologies and techniques, ranging from the tried and tested to completely novel approaches. This blog explores the different approaches being used for obtaining an approved and licenced vaccine.

Figure 1. The number of COVID-19 vaccines at different stages of clinical development and the six front-runners
Source: Milken Institute. Updated as of 26 August 2020.6

The different approaches employed in the search for a COVID-19 vaccine
All vaccines under development aim to expose the body to SARS-CoV-2 antigens to induce an immune response that can stop or eliminate the virus if a person becomes infected, without causing the disease.7 Figure 2 shows an overview of the different vaccine development approaches currently being used against COVID-19. The tried and tested methods include classical virus vaccines and protein-based vaccines, while the novel approaches include the use of nucleic acid and viral vector vaccines. Each approach offers a unique combination of advantages and limitations and we will likely benefit from having more than one approved type of vaccine to be manufactured and distributed around the globe.

Figure 2. Schematics of the different vaccine platforms in development against COVID-19.
Source: Nature.8

Virus vaccines
Virus-based vaccines can consist of live-attenuated virus or a non-infectious, inactivated virus. Live-attenuated viruses are reproducing, weakened viruses that are less able to cause the disease. Even though the technology to produce this type of vaccine is mature and tested, it bears the risks of transfer of the virus and/or reversion to the pathogenic form, reactivation in more immune-compromised individuals or recombination with more closely-related viruses circulating in the population.9

Virus vaccines can be formulated with chemically or heat-inactivated virus, which are incapable of replication and are safer than live-attenuated virus vaccines.10 Three of the front-runners currently in Phase III trials use this classical approach.11 However, their inactivation results in lower immunogenicity and are, therefore, more likely to require adjuvants to stimulate the immune system and multiple-dose regimens to create longer-lasting immunity.12 The main limitation of this type of vaccine is perhaps the requirement of large quantities of infectious virus for its production. Both live-attenuated and inactivated virus vaccines require cold chain transportation, which can pose a significant challenge to global distribution.

Protein-based vaccines
Protein-based vaccines can consist of fragments of protein or protein shells that present the antigens on the SARS-CoV-2 outer coat. These proteins or fragments thereof are structural viral components that can provoke protective immune responses. However, to trigger strong immune response they require the addition of immune-stimulating adjuvant molecules, as well as multiple dose regimens.13 Three candidate vaccines that use protein subunits are currently in phase I/II or II trials.14

Viral vector vaccines
Viral-vector vaccines are made up of a weakened recombinant virus (the viral vector) that cannot cause the disease.15 There are two types of viral vector vaccines: replicating and non-replicating. Replicating viral-vectors infect cells in which they produce the vaccine antigen and replicate to produce more viral-vectors to infect new cells.16 Such vaccines tend to be safe and can produce a strong immune response, with a single dose possibly being sufficient for protection. The main limitation is that existing immunity to the viral vector can dampen its effectiveness.17

Non-replicating viral-vectors, in turn, can enter cells and trigger endogenous vaccine antigen production, but no new viral vectors are formed.18 Booster shots might be required to induce long-lasting immunity with this type of vaccine. Currently, no licensed vaccines use this approach, but the technology has been used in next generation gene therapies.19 There are four non-replicating viral-vector vaccines currently in clinical stages, one of which is a front-runner in phase III trials.20

Nucleic acid vaccines
Nucleic acid vaccines can be made of DNA or RNA constructs which, after being up-taken, instruct the cells to produce the vaccine antigen.21 Even though no licensed vaccines use this technology, nucleic acid vaccines are considered safe and easy to produce, as it only requires genetic material, not the virus.22 Due to the ease in their manufacturing process, it is not surprising to see that there are 10 nucleic acid vaccines in the pipeline, two of which (RNA-based) are front-runners in phase II/III or III.23 Importantly, these can quickly be adapted to new emerging viruses.24

Recent reports and articles have shown that naturally occurring antibody levels drop in COVID-19 patients a couple of months after infection.25,26 However, this does not necessarily jeopardise the efficacy of the vaccines currently being developed and clinically tested. Indeed, one of the biggest advantages of having different approaches being tested is that it increases our chances of getting the right combination of elements that provoke effective and long-lasting immunity, compared to our body’s natural response. In some cases, science can be more effective than nature, as is the case with the HPV vaccine compared to natural infection.27 Ideally, these vaccines should result in long-lasting immunity, but, considering our experience with annual flu vaccination, periodic (e.g. annual) booster shots could also be a feasible and effective option.28

To be effective, vaccination should prevent severe disease and/or lead to complete elimination or significant reduction of transmission within the population. Due to the unprecedented scale of the current pandemic, licensed COVID-19 vaccines will need to be manufactured in large quantities and distributed safely to all corners of the world. While this presents an enormous challenge for the biopharma industry and governments and their public health systems, it will also require a re-evaluation of the role of the various stakeholders including ensuring that governments and key stakeholders are equipped to respond effectively to any future pandemics. Hopefully the international initiatives and collaborative efforts to deliver safe vaccines for COVID-19 will provide lessons that will shape the vaccine development landscape and bolster our preparedness for future epidemics or pandemics.


Maria João Cruz - Research Analyst, Centre for Health Solutions

Maria João Cruz is a Research Analyst for The Centre for Health Solutions, the independent research hub of the Health Care and Life Sciences team. At the Centre she conducts rigorous analysis and research to generate insights that support the practice across life sciences and health care. Maria João has a PhD in Bioengineering and over 10 years of experience in scientific research.

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