COVID-19 vaccines: how do they work?

The COVID-19 pandemic is still continuing around the world, with many cities and countries having to re-implement lockdowns as they enter their second waves of infection. Scientific research on COVID-19 is continuing at a frantic pace to develop vaccines that will eliminate COVID-19 and stop the cycle of lockdowns. Many countries, including Australia and Canada, have secured COVID-19 vaccines to distribute to their populations pending successful clinical trials and regulatory approval. Although all COVID-19 vaccines aim to stimulate an immune response and memory against the SARS-CoV-2 virus (the virus that causes COVID-19), they vary in their composition with different vaccine types having distinct advantages and disadvantages. In this blog post, I will explain how vaccines work in protecting the person against COVID-19. I will then discuss the vaccine types being developed to immunize people against COVID-19 and outline the advantages and disadvantages of each one.

The immune response to the SARS-CoV-2 virus

SARS-CoV-2 is an enveloped RNA virus that is studded with Spike (S) proteins. S protein is a trimeric protein consisting of the “bulb” S1 subunit that mediates receptor binding and the “stalk” S2 subunit that assists in viral entry. The receptor binding domain (RBD) within the S1 subunit binds to angiotensin-converting enzyme 2 (ACE2) on host cells (Figure 1A). Following receptor binding, enzymes from the host cell cleave the S protein, leading to the fusion of viral and host cell membranes to mediate viral entry and replication. It is the S protein that is present, in one form or another, in most COVID-19 vaccines to protect people against infection.

The body mounts a protective immune response to prevent the virus from killing the person. While the innate immune system acts to restrict the spread of infection around the body, the adaptive immune system sets itself up to eliminate the SARS-CoV-2 virus. The immune response is mostly associated with the production of antibodies against the SARS-CoV-2 virus. Antibodies are proteins that bind to surface proteins of the SARS-CoV-2 virus, specifically the RBD of the S protein (Figure 1B). This neutralises the virus to prevent it from binding to ACE2 to infect cells. The neutralised viruses outside the cells are consumed and degraded by white blood cells such as macrophages, eliminating the virus.

The body also activates two types of T cells to boost the immune response. Helper T cells enhance different areas of the immune response such as helping B cells produce stronger antibodies against the SARS-CoV-2 virus (Figure 2A). In contrast, killer T cells recognise and kill virus-infected cells, halting further production of the SARS-CoV-2 virus (Figure 2B).

Depending on how many times the body is exposed to the virus, the body can generate two types of immune responses (Figure 3). The body generates a primary immune response when exposed to the SARS-CoV-2 virus for the first time. The primary immune response is slow and weak as it takes days for the body to generate enough antibodies and T cells to eliminate the virus. However, the body generates long-lasting memory B and T cells that “remember” the SARS-CoV-2 virus, generating immune memory. When the virus enters the body for the second time, the body develop a secondary immune response. The secondary immune response is stronger and quicker than the primary immune response as memory B and T cells are rapidly activated. This results in higher antibody concentrations and T cell counts around the body to eliminate the virus more quickly, reducing the symptoms and severity of COVID-19. In addition, more memory B and T cells are produced after infection which strengthens memory of the SARS-CoV-2 virus. It is the development of immune memory that is key to how a vaccine works.

How do vaccines work?

The person can develop immunity against the SARS-CoV-2 virus by becoming infected. If the person survives the infection, the body can develop long-lasting immunity to the SARS-CoV-2 virus, potentially protecting them against future infection. Natural infection is undesirable; however, as there is the risk that COVID-19 can kill the person due to the immune system becoming hyperactive and damaging cells and organs around the body. Natural infection may also lead to long-term morbidity consisting of persistent symptoms such as fatigue even after the virus is eliminated.

This is where vaccines come in. A vaccine contains a non-infective (attenuated) version of the pathogen or bits of the pathogen (antigens) that are injected into the body. The body develops a primary immune response to the vaccine, producing memory B and T cells to generate immune memory against the SARS-CoV-2 virus. This occurs without the vaccine reproducing natural infection. By developing immune memory while the vaccine is present, the body is protected against COVID-19 as the immune system is primed to mount a secondary immune response when re-exposed to the SARS-CoV-2 virus.

There are a lot of factors that must be considered when designing a COVID-19 vaccine (Figure 4). The vaccine must:

1. Produce the correct immune response: the vaccine must induce both antibody and T cell responses to neutralize and eliminate the virus. Conversely, the vaccine must neither develop immune memory that reduces the immune system’s ability to respond to the SARS-CoV-2 virus nor produce a hyperactive immune response that will damage cells and organs around the body, killing the person.
2. Be stable: ideally, the vaccine is formulated so that it can be stored at room temperature. This eliminates the need to maintain cold storage facilities to keep the vaccine stable, allowing the vaccine to be distributed to more remote areas of the world.
3. Be safe: the vaccine must induce no or few side effects and must not cause serious adverse reactions that puts the person at risk of hospitalization or death.
4. Be easy to administer: Vaccines given orally or nasally are ideal as they are easy to administer. Most vaccines are given intramuscularly, where the vaccine is injected into the muscle. Intramuscular vaccines are not ideal as they can only be performed by a trained doctor or nurse, require needles and syringes and are painful.
5. Be scalable: given that millions of doses must be produced to vaccinate everyone in the country, the vaccine should be easy to produce and scale up in manufacturing.
6. Be cheap to produce and distribute: the cost of producing and distributing the vaccine must be kept low so that low- and middle-income countries can afford to buy the vaccine in bulk to vaccinate their population and eliminate COVID-19.

The following sections will explain the types of vaccines that are produced against COVID-19 (Figure 5) and outline the advantages and disadvantages of each one.

Live attenuated vaccines

Live attenuated vaccines contain a live but less infective form of the pathogen. These vaccines have all the components of the original pathogen, but they possess mutations that reduce their ability to replicate inside the body (represented by black sections in Figure 5A), so they will not reproduce natural infection. It is a proven vaccine technology used to vaccinate people against many infections such as polio, tuberculosis and chicken pox. As of the beginning of September 2020; however, only three COVID-19 vaccines are live attenuated vaccines with none entering clinical trials. One of these is being developed in Griffith University, where parts of the SARS-CoV-2 genome are mutated to reduce but not abolish the ability of the SARS-CoV-2 virus to replicate in human cells.

Live-attenuated vaccines present advantages to combating COVID-19. A single dose of the vaccine is sufficient to protect the person against COVID-19 as it has all the components of the original SARS-CoV-2 virus to generate strong antibody and T cell responses. This generates long-lasting immunity to COVID-19 due to the mass proliferation of memory B and T cells. At the same time, a live attenuated COVID-19 vaccine, once approved, can be quickly produced at scale as existing methods and facilities are available to produce live attenuated vaccines.

There are also disadvantages associated with a live attenuated COVID-19 vaccine. The production of live attenuated vaccines requires biosafety-level facilities to safely produce the vaccine. Cold storage facilities are also required to maintain stability of a live attenuated COVID-19 vaccine, limiting the global distribution of the vaccine. Also, a live attenuated COVID-19 vaccine cannot be given to immunocompromised or immunosuppressed patients as the attenuated SARS-CoV-2 virus can slowly replicate, exceeding the immune system’s ability to contain the pathogen. Lastly, there is the risk that the attenuated SARS-CoV-2 virus can accumulate mutations while it replicates to revert back to its infective form, reproducing infection. This is the case for the oral polio vaccine. As it accumulates mutations inside the body, the vaccine can become pathogenic to humans. causing vaccine-derived polio.

Viral vector vaccines

Viral vector vaccines are similar to live-attenuated vaccines in that they use an attenuated virus. However, the attenuated virus carries a foreign gene in their genome representing the antigen of interest (the blue line in Figure 5B). When the virus infects a cell, they administer the foreign gene into the cell. This allows the cell to produce and show the antigen on the cell surface to stimulate an immune response (Figure 6). The infected cell may also slowly reproduce the virus which allows more cells to become infected and display the antigen on its surface.

Viral vector vaccines are a new vaccine technology with only one vaccine of this type currently approved for clinical use. Dengvaxia is a dengue vaccine that consists of two genes from the dengue virus being expressed in an attenuated yellow fever 17D viral strain. The vaccine is only given to people who were previously infected with dengue as it has been shown to cause severe complications and dengue infection among uninfected people. Nevertheless, two well-known COVID-19 vaccine candidates are viral vectors, both of them possessing the foreign gene for the S protein. AZD1222, developed by Oxford University, contains a gene for the whole S protein that is expressed in a non-replicating chimpanzee adenovirus. Gam COVID Vac is another COVID-19 viral vector vaccine that is developed by Gamaleya Research Institute, Russia. The vaccine consists of the gene for the whole S protein that is contained in two different recombinant human adenoviruses administered separately.

Similar to live-attenuated vaccines, viral vector vaccines can stimulate strong antibody and T cell responses as the virus is able to (slowly) infect cells to produce and display the S protein on the cell surface. This allows both B and T cells to be activated, producing strong immune responses and memory. There are some obstacles, though, in approving viral vector vaccines for use in humans. Like live-attenuated vaccines, viral vector vaccines cannot be used in immunocompromised or immunosuppressed people as the immune system is unable to contain the slow replication of the viral vector. The viral vector vaccine may also be less effective in people with pre-existing antibodies against the viral vector, preventing it from infecting cells to generate immune memory against the SARS-CoV-2 virus. Lastly, viral vector vaccines are complicated to produce. Not only does it require specialized facilities to produce the viral vector vaccine and maintain its purity, but as it is considered a genetically modified organism (GMO) that carries a potential risk to the environment, it is also subject to strict environmental regulation and risk management.

Inactivated vaccines

Evolving from live-attenuated vaccines that are able to (slowly) replicate in the body, inactivated vaccines contain a whole pathogen that is killed or inactivated by chemical, heat or radiation (represented by diagonal lines in Figure 5C). This eliminates the possibility of the pathogen replicating and possibly causing infection, yet the vaccine still has all the components of the original pathogen to induce a memory response. Various inactivated vaccines are available to vaccinate people against infections such as cholera and hepatitis A. Following in these footsteps is CoronaVac, produced by Sinovac R&D Co. CoronaVac contains the inactivated SARS-CoV-2 virus that is combined with alum (aluminium salt). Alum acts as an adjuvant to stimulate immune responses against the vaccine.

Inactivated vaccines are considered safer to use than live-attenuated vaccines with fewer side effects. This is because the vaccine components cannot replicate inside the body, eliminating the possibility of infection. Inactivated vaccines can also be stored at room temperature as the pathogen is dead and non-replicative. This eliminates the need for refrigeration, allowing the vaccine to be distributed to more remote areas of the world.

On the other hand, as the inactivated pathogen cannot replicate inside the body, more than one dose of the inactivated vaccine is required to give the body time to develop immune memory against the SARS-CoV-2 virus. In addition, specialized biosafety-level facilities are needed to firstly grow the pathogen and then inactivate it at scale. Lastly, inactivation of the pathogen may alter the shape of the antigens which may be different from the original version. Hence, the body may not generate the correct immune memory response against the original SARS-CoV-2 virus.

Subunit vaccines

Subunit vaccines take parts of the pathogen (antigens) that simulate an immune response and inject them into the body. Most subunit vaccines consist of proteins from the pathogen (such as the SARS-CoV-2 S protein in Figure 5D), but they can also be fragments of bacterial toxins (toxoids) or pathogenic components such as the cell wall. Many clinically approved subunit vaccines are available with a key one being the DTP vaccine. This vaccine consists of diphtheria and tetanus toxoids and pertussis toxoids and proteins, immunizing the person against diphtheria, tetanus and pertussis. Two of the COVID-19 vaccine candidates are subunit vaccines: NVX-CoV2373 developed by Novavax and SCB-2019 developed by Clover Biopharma. Both vaccines contain the whole S protein of the SARS-CoV-2 virus combined with an adjuvant, a chemical that enhances the immune response to the vaccine.

Subunit vaccines produce strong antibody responses as the antigens are collected, processed and presented to B cells to stimulate antibody production. However, they are less effective in producing strong T cell responses as cells are not infected. Hence, the immune and memory responses induced by subunits vaccines are weaker compared to other vaccines. Nevertheless, they are safe to administer as the whole pathogen is not injected, so it will not cause infection. Lastly, they are simpler and cheaper to produce as only parts of the pathogen need to be produced.

DNA and RNA vaccines

DNA and RNA vaccines consist of DNA or RNA encoding the antigen of interest (represented by blue sections in Figure 5E-F). Contained by itself or placed under a vehicle such as a nanoparticle, once administered the DNA or RNA are taken up by host cells which produce and show the antigen on its cell surface, stimulating an antibody and T cell response (Figure 7). Despite the absence of clinically approved DNA and RNA vaccines, research is ongoing in the USA to develop DNA and RNA vaccines against COVID-19. Moderna is developing the RNA vaccine mRNA-1273 encapsulated in a lipid nanoparticle while Inovio Pharma USA is developing the DNA vaccine INO-4800. Both vaccines carry the foreign gene for whole S protein.

DNA and RNA vaccines strike the balance between generating effective immune responses and ease of production. DNA and RNA vaccines can induce strong cell-mediated and antibody immune responses as once the DNA or RNA is taken up by the cell, the cell can produce and show the protein on the cell surface to stimulate an immune response. At the same time, DNA and RNA vaccines are cheaper to produce as genetic material is easy to mass produce. They are also safe to administer on immunosuppressed or immunocompromised people as no pathogenic or infectious components are injected, eliminating the risk of infection.

DNA and RNA vaccines, however, present some challenges. As there are currently no approved DNA or RNA vaccines, it is unclear how effective they will be in vaccinating a population against COVID-19 or how quickly they can be scaled up. In addition, naked genetic material alone is unlikely to produce strong immune responses and memory as they can be quickly degraded outside cells and need to cross cell membranes to produce and shuttle the antigen on the cell surface. There are also safety concerns that DNA or RNA vaccines can persist in the body for a long period of time and may incorporate into the host’s genome. This can mutate cells, leading to the development of tumour cells.

Conclusion

A variety of COVID-19 vaccines are being developed around the world. All of them share one thing in common: they all stimulate a primary immune response so that the body can develop memory B and T cells against the SARS-CoV-2 virus. The development of immune memory by vaccines is what will protect the person against subsequent COVID-19 infection.

Each COVID-19 vaccine has distinct advantages and disadvantages, but the development of different COVID-19 vaccines provides some redundancy. In case a vaccine is unsafe in humans or fails to protect people against COVID-19, the world has other COVID-19 vaccines that it can trial and produce. It is this pursuit of multiple vaccines that will allow the global population to be immunised sooner, allowing COVID-19 to be eliminated so that the world can start to recover from the pandemic.