Vaccines have been in production for hundreds of years and all of the different forms of technology or so called ‘platforms’ have been applied to the worldwide efforts to produce a SARS-CoV-2 or COVID-19 vaccine. No approach is off the table as researchers and pharmaceutical companies combine efforts to limit the pandemic through immunisation. Hence, there are multiple vaccine approaches utilised by the over 200 COVID-19 vaccines currently in the pipeline. In particular, there are several newer and novel approaches that have shown great promise in advanced (Phase 3) clinical trials. If these newer approaches prove effective, we are likely to see them widely used in the future.

Most of these vaccines build on already existing vaccine technology, many of which have already been shown to be safe in tens of thousands of people. Results from early clinical trials and the interim results from Phase 3 trials of a number of candidates show that the majority of these vaccines are safe, immunogenic and likely to be effective in both preventing COVID-19 infection, as well as severe COVID-19 disease.

This article provides a summary of the different approaches and the most advanced COVID-19 vaccines utilising these different platforms. The majority of the vaccines in advanced trials, require two doses to provide clinical protection against the SARS-CoV-2 virus.

Traditional vaccine approaches

Inactivated virus vaccines

Inactivated vaccines are created by killing or deactivating the virus so that it is unable to replicate. The whole virus or a subunit of the virus can be used. This approach has been used for decades, such as with hepatitis A and inactivated polio vaccines.

These vaccines are generally safer than live vaccines as they can be given to everyone, including immunocompromised people. However, the immune response induced by this mechanism alone may not be as strong or long-lasting and booster doses or an adjuvant may be required (additional vaccine components that boost the immune response).

There are currently four inactivated COVID-19 vaccines in Phase 3 trials. Three are developed by Chinese companies (Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm and Sinovac Biotech) and one is being developed by the Indian company Bharat Biotech. There are several more in pre-clinical and early clinical trials.

Protein-based vaccines

Part of the pathogen that induces an immune response is used to make the vaccine; this part may be a whole protein or fragments of the protein. These vaccines are safe, relatively simple to make and are cheaper to produce. However, multiple doses or an adjuvant is often required to induce an adequate immune response. This method is used to make hepatitis B vaccines.

This is the most common approach for COVID-19 vaccines, with dozens in pre-clinical and clinical trials. There are two in advanced Phase 3 clinical trials, developed by US-based Novavax and Canadian-based Medicago. The most common component of the SARS-CoV-2 virus used to make these vaccines is the spike protein. Spike proteins play a key role in pathogenesis; allowing entry into human host cells and hence subsequent infection.

One disadvantage of using whole protein vaccines is that they have an unstable structure that may lead to loss of immunogenicity. Novel technologies, such as the molecular clamp technique used in the University of Queensland COVID-19 vaccine, have been developed to stabilise the spike protein. This vaccine previously had an agreement with the Australian government, however will no longer be proceeding to Phase 3 trials.

Two other protein-based vaccines are being developed or tested in Australia. Flinders University and an Australia biotech company, Vaxine, are developing a vaccine based on the company’s earlier severe acute respiratory syndrome (SARS) vaccine which was effective in animal studies. Early trials were conducted in Adelaide and Phase 3 trials are due to begin overseas by the end of 2020. The other is a vaccine developed by Chinese-based Clover Biopharmaceuticals which started Phase 1 trials in Perth in June 2020.

Novel vaccine approaches

In the past few decades, vaccine technology has a made significant advances particularly in relation to genetic technology. These newer vaccines pave the way for more efficient and timely vaccine production as soon as the genetic sequence of a new pathogen is known.

Nanoparticle-based and virus-like particles vaccines

Nanoparticle-based vaccines have received increasing interest in recent years due to their good safety profile and high immunogenic potential. Nanoparticle vaccines are constructed by attaching selected key components of a pathogen (such as the COVID-19 spike protein or viral DNA) to an engineered nanoparticle (nanocarrier). This nanoparticle is commonly an engineered virus-like particle (a molecule that mimics the virus but is not infectious). These nanoparticles are highly stable and less prone to degradation than traditional protein vaccines. The human papillomavirus (HPV) vaccine is an example of this approach.

The Novavax COVID-19 vaccine is a nanoparticle vaccine which contains pieces of the spike protein; hence, it can also be listed as a protein-based vaccine. Early clinical trials were performed in Melbourne and Brisbane. Phase 3 trials are underway in the UK. Novavax has signed an agreement with the Australian government to provide 40 million doses during 2021, if the vaccine is successful.

Genetic vaccines

Genetic vaccines deliver one or more of the pathogen’s genes to provoke an immune response. There are two types, DNA and messenger RNA (mRNA) vaccines. DNA is the original genetic sequence which codes for all components of the virus. Firstly, DNA is converted into mRNA and then, mRNA is converted into viral proteins. The immune response is triggered by the production of these viral proteins.

These vaccines can be produced faster than traditional vaccines as development can begin as soon as the genetic sequence of a new pathogen is available. Although DNA and mRNA vaccines have never been licensed before, they have already been under development for other viruses, such as influenza, and have been tested and shown to be safe in Phase 1 and 2 clinical trials.

Due to the instability of DNA and mRNA, these vaccines will be more difficult to transport and store. The majority of other vaccine candidates can be managed using standard cold chain systems, at 2-8°C. The Pfizer COVID-19 vaccine will need storage at -70°C, shipment on dry ice and will only last 24hrs when refrigerated. The Moderna COVID-19 vaccine is be more stable and can be transported at -20°C and stored in a standard vaccine fridge (2-8°C) for 5-days. Australia does not currently have the capacity to make these mRNA vaccines locally.

DNA vaccines may need to be delivered differently from routine injections. Inovio’s COVID-19 DNA vaccine needs to be given intradermally by a device that releases a small electric current to allow entry of the vaccine through the skin. DNA vaccines have not worked as well historically, because it is difficult to get enough DNA introduced to make a strong immune response. Inovio started Phase 2/3 trials in November 2020.

There are theoretical concerns about potential integration into the host’s (vaccine recipient’s) DNA, although the risk of this is extremely very low. The DNA in the vaccine will only enter a small proportion of muscle cells, which cannot replicate, and hence cannot spread to cause mutation or genetic changes in other cells. For mRNA vaccines, this would be impossible. mRNA from a vaccine is only capable of producing proteins and cannot be reversed back into DNA and hence is unable to modify the host DNA. mRNA vaccines have been shown to create a strong immune response, especially compared to DNA vaccines, have the potential for low cost manufacture and a good safety profile.

Moderna was the first company to put a COVID-19 vaccine into human trials in March 2020 and they were also second to release interim results from their Phase 3 trial. These results indicated that their mRNA vaccine had 94.1% vaccine efficacy in preventing COVID-19 disease and also appeared to protect people from severe disease.

The Pfizer/BioNTech mRNA vaccine was the first to present interim data of their Phase 3 trial, indicating it also had 95% vaccine efficacy. On 2 December 2020, the United Kingdom gave emergency authorization to this vaccine. Pfizer/BioNTech has signed an agreement with the Australian government to provide 10 million doses from early 2021, if the vaccine is successful. These doses will be manufactured offshore.

Viral vector vaccines

A virus (viral vector), which doesn’t cause disease in humans, is used to carry part of the pathogen’s DNA into human cells. Some viral vector vaccines enter cells and cause them to make viral proteins (non-replicating viral vectors). Other viral vectors slowly replicate, carrying SARS-CoV-2 proteins on their surface (replicating viral vectors). Replicating viral vectors best mimic natural infection and hence produce a strong immune response and can be used in lower doses.

Human adenoviruses, viruses which cause the common cold, are a commonly used viral vectors for COVID-19 vaccine development. Most encode the spike protein. While adenovirus vectors are well tolerated and highly immunogenic in most people, pre-existing immunity to the viral vector may hamper the immune response to the vaccine. Animal adenoviruses can be used to overcome this; this is utilised by the Oxford University vaccine.

One of the most advanced non-replicating viral vector vaccines is the Oxford University/Astra Zeneca COVID-19 vaccine (AZD1222), which uses a chimpanzee adenovirus vector. This adenovirus vector is unable to cause disease in humans and has been tested for safety in other vaccines for Ebola, Middle East respiratory syndrome (MERS) and influenza. Preliminary analysis of their Phase 3 trial revealed the vaccine had 90% vaccine efficacy, depending on the dosage. Further Phase 3 testing is underway to verify these results. Oxford University/Astra Zeneca have signed an agreement with the Australian government to provide 3.8 million doses from early 2021, if the vaccine is successful. These doses will be manufactured in Australia by CSL.

Another advanced non-replicating viral vector vaccine is the Johnson & Johnson COVID-19 vaccine which utilises an existing human adenovirus vector platform that was used in their Ebola vaccine; which is already approved for use in the general population and has proven to be safe and effective in tens of thousands of people already.

There are two other non-replicating viral vectors in Phase 3 trials, developed by China’s CanSino Biologics and Russia’s Gamaleya Research Institute. There is only one replicating viral vector vaccine candidate in Phase 1 clinical trials, developed by the Institute Pasteur in France. There are over a dozen more in pre-clinical stages which utilise multiple viruses including influenza and measles virus-based vectors.

Other traditional vaccine approaches

Live-attenuated virus vaccines

Live vaccines contain a weakened (attenuated) form of the pathogen that is less capable of replication and is less virulent. Live vaccines induce a strong immune response and provide long-lasting immunity. This method has been used to protect against multiple viruses and is currently used to make the measles, mumps, rubella, chickenpox (varicella) and one rotavirus vaccine. The main disadvantage is that they cannot be given to people who are immunocompromised or pregnant. In addition, they take longer and are more difficult to mass produce because these viruses need to be grown under enhanced biosafety protocols in specialised laboratories.

Due to vaccine safety concerns and the timeline to produce vaccines on this platform, there is currently only one live attenuated COVID-19 vaccine registered to start Phase 1 human trials (developed by New York-based company, Codagenix) and two are in pre-clinical (animal) trials.

The information on this page was updated on 9 December 2020.


Authors: Daniela Say (MVEC Immunisation Fellow) and Nigel Crawford (Director SAEFVIC, Murdoch Children’s Research Institute) 

Date: December 2020

Materials in this section are updated as new information and vaccines become available. The Melbourne Vaccine Education Centre (MVEC) staff regularly reviews materials for accuracy.

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