Types of SARS-CoV-2 vaccines

The majority of the SARS-CoV-2 vaccines are designed to induce immune responses to the spike protein. Expectations from vaccine include induction of neutralizing antibodies and T-cells to – mostly – the spike.

Generally there are many types of vaccines, categorized by the antigen used in their preparation. Their formulations affect how they are used, how they are stored, and how they are administered.

Currently, more than 180 vaccines are globally in development for SARS-CoV-2. Forty are in clinical trials, ten are already in Phase III. Below are the difference types of SARS-CoV-2 vaccines which are being manufactured.

*Different types of SARS-CoV-2 vaccines and their clinical trial phases*

Inactivated vaccines: In this type virus is isolated, grow it in cell culture (e.g. Vero cells) and then harvest and concentrate it (usually by ultracentrifugation). Following that, physically or chemically virus is killed. This has been in use for a very long time and works for many vaccines (e.g. hepatitis A, influenza virus etc.). The virus can’t infect cells anymore but immune system responds to it, mostly by making antibodies. This can be done with SARS-CoV-2 with biosafety level 3 production facility. Several vaccines in China, India and Kazakhstan made this way are being developed with some already far in Phase III.

Live attenuated vaccines: Live attenuated vaccinesare derived from disease-causing pathogens (virus or bacteria) that have been genetically weakened under laboratory conditions. They will grow in a vaccinated individual, but because they are weak, they will cause no or very mild disease. The virus does not make sick but mimic natural infection that triggers an immune response similar as to the pathogenic virus.

Nowadays, there are more ways to do that, e.g. by altering the genetic code so that it doesn’t translate well anymore a technology called codon deoptimization, or by just taking away a gene of the virus that it needs to make us sick. However, coronaviruses are hard to manipulate genetically and there might still risk from these vaccines for people with compromised immune systems.

Examples for live attenuated vaccines are, the measles or yellow fever vaccines, or FluMist, which is the flu vaccine that kids get as nasal spray. They work well. Unfortunately, only three live attenuated vaccines are in development for SARS-CoV-2 and they are far behind.

Recombinant protein vaccines: Gene of a viral antigen will be taken out and that antigen expressed in a suitable system (e.g. bacteria, mammalian cells, insect cells, yeast or even plants). No infectious virus is involved anywhere, making this very safe.

For SARS-CoV-2, the whole spike protein (like Novavax) can be expressed or just the receptor binding domain (RBD) which it the part of the spike that docks to cells or can make virus-like particles.

Vaccines based on this technology work well and are on the market for influenza (FluBlok), hepatitis B and human papilloma virus (HPV). The technology works well and is safe. The frontrunner here is currently Novavax (just entered Phase III in the UK) and Sanofi.

Replication incompetent viral vectors: Genome from another type of virus will be pasted into the gene of desired antigen. Then these vectors will be produced in a suitable cell line. Once they get injected into the vaccine they force some of the cells of the vaccine to make the antigen. Again, in this case the antigen is the spike protein of SARS-CoV-2. Now, this is nothing that is concerning, in fact, SARS-CoV-2 does the same. The difference is, that the viral vectors do not replicate. but just deliver the genetic information for cell to make the antigen which is then recognized by immune cells.

These types of vaccines are licensed for Ebola in the EU and have been considered safe for that purpose. For SARS-CoV-2 some of the vaccines in Phase III trials are in this category including CanSino’s vaccine which is based on an adenovirus 5 vector and AstraZeneca’s vaccine which is based on a chimpanzee adenovirus vector. Adenoviruses are typically cause common colds and GI tract infections but these vectors can’t replicate and therefore are not pathogenic. The problem with the vectors is often, that humans have pre-existing neutralizing antibodies which might intercept the vector before it enters your cells. This is a big problem for AdV5 (CanSino) but AstraZeneca circumvented this by using a virus that is not circulating in humans. However, if the same vector twice, this issue can still occur even if vector used is not prevalent in humans. The huge advantage of these vectors is that they drive very good T-cell responses.

Now, there are other vectors that are replication competent. They have not been genetically gutted but the gene for the antigen of choice has just been added or has replaced a gene from the original virus. Viruses used for this are usually viruses that don’t cause disease in humans or vaccine strains. One such vaccine, again for Ebola and based on the vesicular stomatitis virus (which infects usually cattle) is licensed in the EU and was found to be safe. While there are no leading candidates for those yet for SARS-CoV-2, promising candidates based on a measles vaccine strain have entered clinical trials. Several more are in the preclinical stage. These vectors are usually pretty immunogenic because they trigger innate immune responses when they replicate. But they can be problematic in individuals with compromised immune systems. One way around these are inactivated virus vectors. These are virus vectors that express the target antigen and also display it on the virion. These viruses can be grown, purified and inactivated just like inactivated vaccines, but are of course safer to culture because they are usually harmless. One of these approaches is based on rabies (Bharat Biotech in India), another one is based on Newcastle Disease virus (NDV). The NDV vector is interesting because it can be produced using the influenza virus vaccine production process for which there is a lot of free capacity globally. Peter Palese is working on this with PATH.

DNA vaccines: The gene for the target antigen is inserted into a DNA plasmid under control of a mammalian promotor. This can now be grown up in E. coli in enormous amounts is very cheap and relatively stable. This technology has been used for a long time but hasn’t led to an effective human vaccine yet. The plasmids is then injected and often an electric shock is applied (electroporation) to get the DNA into the cell of the vaccinee. Actually, bringing it into the cell is not enough, it needs to enter the nucleus. Once the DNA is there, mRNA is made – similar to what the virus itself would do – and protein is translated and expressed and then recognized by the immune system. Candidates based on this technology are in clinical trials for SARS-CoV-2 but results haven’t been released yet and progress seems to be slow.

RNA vaccines: They come in two types. mRNA vaccines are basically just mRNA that is delivered to the cells. In contrst, self-replicating RNA consists of usually viral replicons that regenerates itself and the gene for the target antigen, also making mRNA for the target antigen in the process. Both technologies are very similar and new. RNA needs to be delivered, but not to the nucleus, just into the cytosol, making this easier. Usually, the RNA is complexed with lipid nanoparticles which are then injected intramuscularly or intradermal. Once the RNA is in the cell, it is translated into target antigen, in this case spike protein which is then made by the cell and recognized by the immune system. Two of the front-runner vaccines are based on mRNA encapsulated in LNPs. They are developed by Moderna and Pfizer. This is a very cool and new technology. But because it is so new, there might still be kinks in terms of large scale production. Amazingly, these vaccines are made completely in vitro with no living cells involved. One caveat that is already apparent is, that they need to be stored frozen which is a challenge for distribution in the US and certainly also in low and middle income countries.

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Ramya

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