#MSCOVID19: What is vaccination?

Barts-MS rose-tinted-odometer: ★★★★★

What is vaccination? A not so simple medical procedure.

Vaccination is probably one of, if not, the most important scientific/medical inventions in modern history. We need to celebrate it for just that and appreciate the number of saved lives and improved quality of life it has brought to us as a species. 

Now that we broadly know how the immune system functions there is nothing magic, dark or sinister about vaccines and vaccinations work. 

Vaccines simply hijack components of the immune system and fool it into thinking you are being invaded by something foreign and dangerous, e.g viruses, bacteria, parasites, toxins, cancers or foreign bodies. The immune system reacts to the vaccine and rejects the foreign component in the vaccine, but in doing so the immune system remembers the foreign component so in the event of being exposed to it again in the future it can respond to it quickly and prevent it causing too much damage, i.e. disease or some cases death. 

The immune system is primarily responsible for keeping us safe from infectious agents, i.e. parasites (e.g. malaria), bacteria (e.g. pneumococcus) and viruses (e.g. coronaviruses), toxins and cancer. Immune systems are endowed with the ability to remember a previous exposure to an infectious agent. 

Immunological memory is hardwired into our DNA, which includes so-called pathogen-associated or damage-associated recognition receptors (PAMPs or DAMPs). PAMPs and DAMPs are part of our innate immunity and provide a very rapid response to infections. However, as there is an arms race between our immune system and the pathogens, which can mutate and evolve very quickly (e.g. the UK/Kent, South African and Brazilian variants of SARS-CoV-2), we have had to evolve a second or an acquired memory system called adaptive immunity. The latter involves both B-cells or antibodies and T-cells or killer cells that are able to destroy the pathogen using highly targeted mechanisms that in most people don’t cause collateral damage to the body. 

All that a vaccine does is expose the immune system to a part of the whole of the pathogen in the correct context so the immune system remembers the pathogen so that when it is exposed to the pathogen in real-life it can mount a rapid immune response, which prevents you becoming infected and spreading the organism, or prevents you from getting a severe disease or dying from the infection. 

Now there are many different ways of fooling the immune system into remembering the organism. In the past, we used to use related, but benign, viruses. For example, immunity to cowpox, a live virus from cows, cross-reacted with the more dangerous and severe smallpox virus to protect milkmaidens from getting smallpox. This is how Jenner identified and created the original smallpox vaccine. Following Jenner’s smallpox vaccine, the scientific community developed the ability to attenuate viral and bacterial strains in the laboratory, i.e. to create mutant strains that didn’t cause disease, but were similar enough to the original organism to generate a protective immune response. This is how the medical community tackled polio, measles, mumps, rubella, TB, yellow fever and influenzae. This group of vaccines are referred to as LAVs or live-attenuated vaccine strains. 

The problem with LAVs is that the organisms have the ability to mutate back to being dangerous and can cause vaccine strain outbreaks, which has happened many times with the oral polio vaccine. This is why LAVs have in general fallen out of favour. I am not aware of any LAVs being developed for coronavirus; mainly because it is an outdated technology. 

Another way of developing vaccines is to grow the organism in the laboratory and then inactivate or kill them and then to administer either the whole killed organism or a part of it as a vaccine. This is how the seasonal flu virus is currently made. The current circulating strains are cultured in chicken eggs and then the eggs are broken and processed to extract the important surface proteins to go into the vaccine. One of the Chinese vaccines that is currently been tested in COVID-19 uses the whole SARS-CoV-2 virus as an immunogen. 

The term immunogen simply refers to the component of the vaccine you want the immune system to respond to, for example, the spike or surface protein on the coronavirus. When we make vaccines that only have one or a limited number of immunogens we call this a component vaccine. 

Now that we have developed so recombinant protein technology we don’t have to culture live and often very dangerous organisms, but instead engineer other organisms to make the immunogen in large quantities. To do this we alter the genomes of bacteria, mammalian cells, whole animals or even plants to make the protein we want. For example, we can use E. coli bacteria, Chinese hamster ovarian cells, monkey cells or even insect cells to make proteins. The choice of the type of cell is important as many immunogens have sugar molecules on them and cells from different species add sugar molecules in different configurations and combinations. E. coli, for example, does not have the necessary molecular pathways to add sugar molecules to proteins.

A, relatively, new technology is to create genetically modified whole complex organisms that produce your protein of choice. One vaccine company has created a tobacco plant that produced the protein for the hepatitis B vaccine. You then grow the tobacco plant and extract the hepatitis B surface antigen from tobacco leaves. Another company has created a breed of goat that expresses and produces the vaccine immunogen in breast milk. All you have to do is milk these goats and extract the immunogen from their milk. 

Many of the SARS-CoV-2 component vaccines are using standard cell-based methods to produce vast quantities of the immunogen, which at present are mainly targeting the SARS-CoV-2 spike protein. The recent positive Novavax coronavirus vaccine is using spike protein manufactured using insect cells. 

Component vaccines are not that immunogenic unless they are combined with an adjuvant. Adjuvants are substances that enhance the immune system’s response to the vaccine. Adjuvants are often referred to as the immunologist’s dirty little secret. The reason for this is we simply didn’t know how many of the early adjuvants worked. This is not the case anymore and the newer generation of adjuvants that are being used in component vaccines are well defined in terms of their mode of action and are safe.

Some scientists have used molecular biology to engineer other relatively benign viruses so that they make immunogens of other viruses. Instead of making the protein in the laboratory, you produce infectious viruses, that then make the protein in your body. You infect people with these engineered viruses, which are also called vectors, as part of the benign infection your own cells make the protein or immunogen that your immune system then responds to. 

Vaccinia virus used to be the most commonly used virus, but vaccinologists have moved onto adenovirus one of the viruses that cause the common cold.  The Russian sputnik COVID-19 vaccine uses a human adenovirus as the vector. The Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus vector. The problem with using these types of vaccines is that if your immune system has seen the virus in the past, i.e. from natural wild-type viral infection, your immune system reacts to and rejects the vaccine virus before it can infect enough cells to make the necessary quantity of immunogen to be effective. This is why the Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus, which humans are unlikely to have been exposed to in the past. The immune response to the vector itself has implications for booster and additional vaccine using the same technology; i.e. it is likely that boosters and new vaccines using the same vector will be less effective in the future, because of immunity against the vector itself. 

Please note these viral vector vaccines are relying on the virus to infect cells and then use the cells own machinery to manufacture the immunogen. Because these vaccines are an actual infection these vaccines don’t need adjuvants. The final trick with these viral vector vaccines is to create disabled viruses, i.e. viruses that lack the ability to replicate and cause ongoing infection. This is important to prevent the viral vector itself causing an infection in the host or recipient of the vaccine. This is also the reason why the Oxford-AstraZeneca vaccine is not referred to as a live viral vaccine. 

Finally, why waste time with viruses and simply give the viral message without the virus. This is how DNA and RNA vaccines work. You package the necessary code for the immunogen in a DNA plasmid or piece of RNA that is then transcribed into the necessary proteins to induce an immune response. 

Do RNA and DNA vaccines need adjuvant? The cell sees foreign RNA itself as being foreign as being potentially from a virus, which acts via internal danger signalling pathways to alert the immune system to the possibility of an infection. The DNA vaccines incorporate segments of DNA that fool the cell into thinking this DNA is from a bacterium, which also stimulates specific danger signalling pathways telling the immune system there is an infection. This is why RNA and DNA vaccines don’t require additional adjuvants. 

Please be aware that adenoviral vaccines, such as the Russian Sputnik and the Oxford-AstraZeneca vaccines, the DNA vaccine and the RNA vaccines don’t contain the code for manufacturing the necessary enzymes that insert DNA into the genome. The latter is unique to so-called retroviruses such as HIV. Therefore, these coronavirus vaccines don’t affect the human genome and won’t affect the germline, i.e. DNA transmitted via the eggs in the ovary of the sperm in the testes. All that these vaccines do is highjack the cells protein synthesis machinery to make SARS-CoV-2 spike protein and to tell the immune system that there is an infection. This then allows the immune system to make both B-cell or antibody and T-cell responses to coronavirus and protect that individual from being infected or becoming ill from wild-type infection. 

I want to stress that the short summary above represents centuries of research and discovery and that vaccinology is now using cutting edge molecular biology. The rapid development of the DNA, RNA and adenoviral vector vaccines have changed vaccine development for good and I anticipate these becoming the norm for future vaccines. 

I hope the above summary explains how vaccines have developed and debunks the myths about what they are and how they work. Instead of us accepting off-the-wall conspiracy theories about vaccines and what they do please join me in celebrating their success and what they offer mankind.

One of my driving ambitions is to see an EBV vaccine licensed to prevent MS. If you and the general population are not prepared to trust vaccines and the science behind their development, who is going to want their child to have an EBV vaccine to prevent MS, infectious mononucleosis and many different types of EBV-associated cancers?  

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211