Sidebar: The Facts on Vax

This article was reviewed by Dr. Brett Finlay, one of our subject matter experts.

Welcome to the third immunology issue of Sidebar! If you haven’t browsed through my previous articles introducing the two arms of the immune system and going over the battle tactics of B cells and T cells, I would highly recommend you give them a thorough read before you start this article. If you only have a couple minutes, you can browse through the TL;DR box below.

To recap from last time, we learned the following about B cells:

(1) B cells express a BCR on their surface.
(2) When its BCR binds to a viral antigen, the B cell will divide into many clones.
(3) B cells will “level up” into plasma cells, and then release their BCRs as antibodies.
(4) Antibodies function by:
➪ Stopping viruses from entering cells.
➪ Encouraging neutrophils to eat viral particles.

We also became familiar with T cells:

(1) T cells express a TCR on their surface.
(2) The TCR will only recognize antigens if they are presented on MHC proteins.
MHC presentation is performed by:
➪ Dendritic cells that have taken up viral antigens.
➪ Virus-infected body cells.
(3) Upon TCR binding to antigens, T cells will become activated and clonally expand.
(4) There are two main flavours of T cells.
➪ Cytotoxic T lymphocytes will directly kill virus-infected cells.
➪ Helper T cells activate B cells and cytotoxic T lymphocytes.

Today, we will be discussing:

(1) How vaccines can prevent disease.
(2) The two main types of vaccines, and their differing stimulation of B and T cells.
(3) The principle behind a couple SARS-CoV-2 vaccine candidates.

As more information is released from ongoing clinical trials, SARS-CoV-2 vaccine development will be discussed further in the Research Re-hashed section of COVID19 Demystified. For now, let’s start with the basics!

Vaccination relies on the generation of immunological memory.

After B and T cells have clonally expanded and responded to an infection, what happens to them once the virus has been cleared? Many of these adaptive immune cells will naturally age and die, but a small number will become very long-lived. These memory B and T cells can “hibernate” in our tissues, or circulate in the bloodstream for years.

Activation of naïve B and T cells can take days or weeks. In contrast, our adaptive memory cells will rapidly reactivate to make antibodies or kill infected cells, as long as we have encountered the invading pathogen before. But what if we don’t want to get infected, not even once? For instance, rabies virus infection is virtually 100% fatal without early treatment¹.

The solution to this dilemma is vaccination! The idea of vaccination is to mimic an initial infection, inducing the production of memory B and T cells but without the cost of severe disease.

There are two main types of viral vaccines, which differ in their stimulation of B and T cells.

Live vaccines contain a whole virus that is capable of infecting your body cells. Inactivated vaccines contain viral particles, or viral protein subunits, both of which are unable to infect your cells. The different compositions of live versus inactivated and subunit vaccines ultimately impact how your memory immune cells are formed.

(1) For both live and inactivated vaccines, B cells will bind their BCR to the whole virus or particular viral proteins. These B cells will eventually generate antibodies.

(2) In the case of live vaccines, productive infection of cells means that viral antigens can be presented on MHC, and T cells will become stimulated. However, with inactivated vaccines, no productive infection of cells occurs. This means that the T cell response may be more diminished ¹¹, although this does not occur in all cases.

So we see that there is a trade-off. It is often more difficult to engineer a live vaccine to be harmless, and it may not be suitable for immunocompromised patients. However, a single dose of a live vaccine can induce strong and lasting immunity with the generation of both memory T cells and B cells. Inactivated vaccines are easier to design safely, but may only drive a B cell response. Because inactivated vaccines induce weaker immunity, many require periodic “boosting” via additional doses.

Live vaccines can be made from a weakened version of the virus, or a genetic hybrid virus.

Attenuated live vaccines are composed of viruses with multiple mutations in their genetic material, altogether reducing their ability to replicate. Historically, such as in the case of the live polio vaccine, these mutations would accumulate randomly as the virus was forced to undergo many life cycles through cells cultured in a Petri dish.

However, it is important to note that most modern live vaccines are not made this way. Recent gene-editing technologies have made it possible to carefully design attenuated viruses, by purposefully inserting specific mutations into the viral genome. I’m not going to go into the details of this genetic engineering here, but if you would like to know more about it in a future article, please get in touch with contact@coviddemystified.com!

Recombinant vector vaccines are rather different, because they are composed of two or more viruses that have been genetically combined to form a hybrid. The promising “Oxford vaccine” ⁷ for SARS-CoV-2 is based on a recombinant vector. Researchers first started with a chimpanzee adenovirus, and then genetically engineered it to prevent it from causing disease in humans. This benign vector backbone was named “ChAdOx1” ^5,6.

In the second step, the researchers inserted the gene for the SARS-CoV-2 spike protein into the ChAdOx1 genome. This resulted in the formation of a recombinant virus, which expresses the SAIn the second step, the researchers inserted the gene for the SARS-CoV-2 spike protein into the ChAdOx1 genome. This resulted in the formation of a recombinant virus, which expresses the SARS-CoV-2 spike protein on its surface, but the rest of its components are derived from ChAdOx1. The goal is to direct an immune response against the SARS-CoV-2 spike protein, but without the induction of disease because the ChAdOx1 backbone is totally harmless.

Inactivated vaccines can be made from the whole viral particle, or selected viral proteins.

There are many subtypes of inactivated vaccines, but the simplest form is “disrupted virions”. A sample of the virus is treated with a chemical called formalin, which cross-links viral proteins. The formalin is removed during purification of the vaccine prior to packaging, so the final product is completely safe. In fact, your annual influenza vaccine is created this way!

Alternatively, some inactivated vaccines are composed of only one particular protein from a virus. For example, the Shingrix vaccine developed by GlaxoSmithKline is based on only the surface protein of varicella zoster virus. The rest of the varicella zoster virion is completely left out.

There are also inactivated vaccines based on “virus-like particles”, such as Gardasil 9 established by Merck. In this case, the capsid protein of human papillomavirus (HPV) will self-assemble into an empty particle, even in the absence of other virion components.

Again, it is important to note that (1) disrupted virions, (2) purified viral proteins, and (3) virus-like particles are all unable to productively infect cells.

The U. S. National Institute of Allergy and Infectious Diseases (NIAID) and the biotechnology company Moderna Inc. have been working on an exciting new “inactivated” vaccine for SARS-CoV-2, called mRNA-1273⁸. I put “inactivated” in quotes because many consider this type of vaccine to make up a novel category of its own. The NIAID/Moderna vaccine is composed of lipid nanoparticles, each enclosing a ribonucleic acid (RNA) molecule encoding only the spike protein of SARS-CoV-2. The idea is that the injected nanoparticles will deliver the RNA to your body cells. Subsequently, your own cells will use this RNA as a template to synthesize the SARS-CoV-2 spike protein.

The advantage of this approach is that your body cells can present the spike protein antigens on MHC. Therefore, even though the NIAID/Moderna vaccine is “inactivated”, it is still capable of generating memory T cells!

What other types of vaccines are being developed against SARS-CoV-2?

As of April 30, 2020, the WHO has reported that there are 8 SARS-CoV-2 vaccines in clinical trials with another 94 candidates in pre-clinical development². The majority of these vaccines are either based on inactivated SARS-CoV-2 proteins, or live recombinant viral vectors. You can browse through the full list here. This Nature news feature also offers a concise summary of current SARS-CoV-2 vaccine efforts.

If you’re unclear on anything that was discussed in this article, the CDC has a fantastic publication covering the basic principles of vaccination, which is written for a lay audience. You can find it here. If you are especially interested in vaccine ingredients and safety, please refer to credible sources such as the CDC or Ontario Ministry of Health.

Thanks for joining me through this immunology crash course!

References

1. Rabies. World Health Organization (2020). Available at: https://www.who.int/news-room/fact-sheets/detail/rabies.
2. Draft landscape of COVID-19 candidate vaccines. World Health Organization (2020). Available at: https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf?ua=1.
3. Callaway, E. The race for coronavirus vaccines: a graphical guide. Nature (2020). Available at: https://www.nature.com/articles/d41586-020-01221-y.
4. Nouën, C. L., Collins, P. L. & Buchholz, U. J. Attenuation of human respiratory viruses by synonymous genome recoding. Frontiers in Immunology 10, (2019).
5. Dicks, M. D. J. et al. A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity. PLoS ONE 7, (2012).
6. Alharbi, N. K. et al. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine 35, 3780–3788 (2017).
7. U. S. National Institutes of Health. A study of a candidate COVID-19 vaccine (COV001). ClinicalTrials.gov (2020). Available at: https://clinicaltrials.gov/ct2/show/NCT04324606?term=vaccine.
8. U. S. National Institutes of Health. Safety and immunogenicity study of 2019-nCoV vaccine (mRNA-1273) for prophylaxis SARS CoV-2 infection (COVID-19). ClinicalTrials.gov (2020). Available at: https://www.clinicaltrials.gov/ct2/show/NCT04283461.
9. Centers for Disease Control and Prevention. Vaccines: Vac-Gen/Additives in Vaccines Fact Sheet. Centers for Disease Control and Prevention (2019). Available at: https://www.cdc.gov/vaccines/vac-gen/additives.htm.
10. Ontario Ministry of Health. Flu vaccine safety and effectiveness. Ontario.ca (2019). Available at: https://www.ontario.ca/page/flu-vaccine-safety-effectiveness.
11. Hamborsky, J., Kroger, A. & Wolfe, C. Epidemiology and prevention of vaccine-preventable diseases. (U.S. Dept. of Health & Human Services, Centers for Disease Control and Prevention, 2015).