The world can’t return to normal without safe and effective vaccines against the SARS-CoV-2 coronavirus along with a coordinated global vaccination programme.

Researchers have been racing to develop potential drugs that could help end the ongoing Covid-19 pandemic. There are currently around 200 vaccine candidates and about a quarter passed preclinical tests and are now undergoing clinical trials.

What’s the difference between the various candidate vaccines?

A pie chart of candidates can be cut several ways. One is to slice it into six uneven pieces according to the technology (or ‘platform’) that’s used to produce the drug. Those six technologies can be grouped into three broader categories: dead or disabled viruses, artificial vectors, and viral components.

Dead or disabled viruses

Traditional vaccines contain a dead or disabled virus, designed to be incapable of causing severe disease while also provoking an immune response that provides protection against the live virus.

1. Live-attenuated viruses

Attenuated means ‘weakened’. Weakening a live virus typically involves reducing its virulence — capacity to cause disease — or ability to replicate through genetic engineering. The virus still infects cells and causes mild symptoms.

For a live-attenuated virus, an obvious safety concern is that the virus might gain genetic changes that enable it to revert back to the more virulent strain. Another worry is that a mistake during manufacturing could produce a defective vaccine and cause a disease outbreak, which once happened with a polio vaccine.

But using a live-attenuated virus has one huge benefit: vaccination resembles natural infection, which usually leads to robust immune responses and a memory of the virus’ antigens that can last for many years.

Live-attenuated vaccines based on SARS-CoV-2 are still undergoing preclinical testing, developed by start-up Codagenix and the Serum Institute of India.

2. Inactivated viruses

Inactivated means ‘dead’ (‘inactivated’ is used because some scientists don’t consider viruses to be alive). The virus will be the one you want to create a vaccine against, such as SARS-CoV-2, which is usually killed with chemicals.

Two Chinese firms have developed vaccines that are being tested for safety and effectiveness in large-scale Phase III clinical trials: ‘CoronaVac’ (previously ‘PiCoVacc’) from Sinovac Biotech and ‘New Crown COVID-19’ from Sinopharm. Both drugs contain inactivated virus, didn’t cause serious adverse side-effects and prompted the immune system to produce antibodies against SARS-CoV-2.

Sinopharm’s experimental vaccine has reportedly been administered to hundreds of thousands of people in China, and both drugs are now being trialled in countries across Asia, South America and the Middle East.

Artificial vectors

Another conventional approach in vaccine design is to artificially create a vehicle or ‘vector’ that can deliver specific parts of a virus to the adaptive immune system, which then learns to target those parts and provides protection.

That immunity is achieved by exposing your body to a molecule that prompts the system to generate antibodies, an antigen, which becomes the target of an immune response. SARS-CoV-2 vaccines aim to target the spike protein on the surface of coronavirus particles — the proteins that allows the virus to invade a cell.

3. Recombinant viruses

A recombinant virus is a vector that combines the target antigen from one virus with the ‘backbone’ from another — unrelated — virus. For SARS-CoV-2, the most common strategy is to put coronavirus spike proteins on an adenovirus backbone.

Recombinant viruses are a double-edged sword: they behave like live-attenuated viruses, so a recombinant vaccine comes with the potential benefits of provoking a robust response from the immune system but also potential costs from causing an artificial infection that might lead to severe symptoms.

A recombinant vaccine might not provoke an adequate immune response in people who have previously been exposed to adenoviruses that infect humans (some cause the common cold), which includes one candidate developed by CanSino Biologics in China and ‘Sputnik V’ from Russia’s Gamaleya National Research Centre — both of which are in Phase III clinical trials and are licensed for use in the military.

To maximize the chance of provoking immune responses, some vaccines are built upon viruses from other species, so humans will have no pre-existing immunity. The most high-profile candidate is ‘AZD1222’, better known as ‘ChAdOx1 nCoV-19’ or simply ‘the Oxford vaccine’ because it was designed by scientists at Oxford University, which will be manufactured by AstraZeneca. AZD1222 is based on a chimpanzee adenovirus and seems to be 70% effective at preventing Covid-19.

Some recombinant viruses can replicate in cells, others cannot — known as being ‘replication-competent’ or ‘replication-incompetent’. One vaccine candidate that contains a replicating virus, developed by pharmaceutical giant Merck, is based on Vesicular Stomatitis Virus (VSV), which infects guinea pigs and other pets.

4. Virus-like particles

A virus-like particle, or VLP, is a structure assembled from viral proteins. It resembles a virus but doesn’t contain the genetic material that would allow the VLP to replicate. For SARS-CoV-2, the VLP obviously includes the spike protein.

One coronavirus-like particle (Co-VLP) vaccine from Medicago has passed Phase I trials to test it’s safe and has entered Phase II to test that it’s effective.

While there are currently few VLPs being developed for Covid-19, the technology is well-established and has been used to produce commercial vaccines against human papillomavirus (HPV) and hepatitis B.

Viral components

All vaccines are ultimately designed to expose the immune system to parts of a virus, not the whole thing, so why not deliver just those parts? That’s the reasoning behind vaccines that only contain spike proteins or spike genes.

5. Proteins

Protein-based vaccines can consist of the full-length spike protein or the key part, the tip of the spike that binds the ACE2 receptor on the surface of a cell — ACE2 is the lock that a coronavirus picks in order to break into the cell.

Manufacturing vaccines containing the protein alone has a practical advantage: researchers don’t have to deal with live coronaviruses, which should be grown inside cells within a biosafety level-3 lab.

A vaccine against only part of the protein — a ‘subunit’ — will be more vulnerable to being rendered useless if random mutations alter the protein, known as ‘antigenic drift‘, but full-length proteins are harder to manufacture. The immune system can recognize either as an antigen.

One candidate vaccine based on protein subunits is ‘NVX-CoV2373’ from Novavax, where the spike subunits are arranged as a rosette structure. It’s similar to a vaccine that’s already been licensed for use, FluBlok, which contains rosettes of protein subunits from the influenza virus.

6. Nucleic acids

Nucleic-acid vaccines contain genetic material, either deoxyribonucleic acid or ribonucleic acid — DNA or RNA. In a coronavirus vaccine, the DNA or RNA carries genetic instructions for producing a spike protein, which is made within cells.

Those spike genes can be carried on rings of DNA called ‘plasmids’, which are easy to manufacture by growing them in bacteria. DNA provokes a relatively weak immune response, however, and can’t simply be injected inside the body — the vaccine must be administered using a special device to force DNA into cells. Four DNA-based candidates are in Phase I or II trials.

The two most famous nucleic-acid vaccines are the drugs being developed by pharmaceutical giant Pfizer, partnered with BioNTech, and Moderna. Pfizer’s ‘BNT162b2’ and Moderna’s ‘mRNA-1273’ both use ‘messenger RNA’ — mRNA — to carry the spike genes and are delivered into cells via a lipid nanoparticle (LNP). The two mRNA vaccines have completed Phase III trials and preliminary results suggests they’re over 90% effective at preventing Covid-19.

As the above examples show, not only there are many potential vaccines but also various approaches. And while some technologies have already provided promising results, it remains to be seen which will actually be able to defeat the virus.