Covid-19 vaccine mechanism and safety

2020 December 21

What’s in the covid-19 vaccine and is it safe? I’ve assembled here the basic information about the proposed vaccine and its safety. There are multiple covid vaccines, which operate in different ways, and so they need to be analyzed individually. These different mechanisms are referred to as vaccine platforms. I will be focusing on questions of whether these vaccines can cause the disease or latent long-term negative effects, as these are the easiest to answer with confidence. Indeed most of the vaccines are totally incapable of causing the disease, as no sars-cov-2 is used in any step of their manufacture! A more detailed discussion on vaccine safety is at the end.

While the various mechanisms of action are straightforward to understand, I am not an expert in biology or medicine. Therefore my endorsement of their safety is based not just on my own limited understanding, but also on the enthusiastic endorsements given by leading infectious disease experts, whose assessment is made on the basis of a deep theoretical understanding together with extensive testing. You should check with experts and authorities before acting on any information here.

While all of the vaccine platforms discussed below are acceptably safe, they may vary considerably in other factors such as effectiveness (either short-term or long-term), cost of manufacture, speed of manufacture, short-term side effects like sore arm or fever, difficulty of storage and administration, and dependency on having a massive stockpile of 100s of millions of chicken eggs; these are some of the factors that motivate new platform development. I won’t examine these issues, particularly short-term side effects.

Structure of sars-cov-2 and other coronaviruses. The outside of the virus is a fatty envelope, which can be destroyed by soap, and contains four different types of proteins embedded in it. The spike protein is used to bind to cells, and is also the main target of the immune system because it physically protrudes the most. Inside of the envelope is a helical capsid that holds the virus genome as positive-sense single-stranded RNA, functionally similar to mRNA.

(If you are using dark mode, note that the labels are in black text, so open the image in a separate tab to read them.)

Lists of candidate vaccines

Wikipedia has the easiest to understand list of covid-19 vaccine candidates. The New York Times vaccine tracker contains slightly more in-depth information about some vaccines, as well as an accessible explanation of how mRNA vaccines work. The WHO vaccine candidate spreadsheet appears to be more comprehensive, especially for vaccines in early phases, as well as containing links to studies on the candidates, but is harder to read and doesn’t include explanatory exposition. A spreadsheet by the Milken Institute seems to be similarly comprehensive. The New York Times tracker lists several candidates as being in a later phase than the other sources.

Persistent adaptive immunity

The adaptive immune system allows the body to learn to recognize specific molecules as foreign and to respond by aggressively attacking those molecules in the future. A molecule that triggers such a response is called an antigen. It takes about 5 to 7 days after exposure to large amounts of a foreign molecule for the system to learn to recognize it.

During an infection, the immune system adapts to some molecule found in the pathogen. Vaccines work by exposing the body to that molecule, thus triggering the adaptive immune system without an infection. The immune system’s response to the vaccine can result in mild fever or other symptoms despite the absence of infection.

Vaccine platforms

Dead, attenuated, and heterologous vaccines

Synthesizing molecules from viruses and bacteria can be extremely difficult, so often the easiest way to make them is to simply grow the pathogen in some host. After harvesting from the host, the pathogen is killed off or weakened (“attenuated”) before being put in the vaccine so that the vaccine doesn’t cause an infection.

A well-known vaccine of this type is the flu vaccine. Until 2019 the flu vaccine was grown in chicken eggs; for this reason the US keeps a strategic stockpile of secret chickens.

Attenuation is performed by growing the pathogen in an environment unlike the natural host; for the flu, this involves successively colder temperatures until the virus can only survive in the upper respiratory system.

Vaccines of this type always require a sample of the pathogen itself (or a close relative, for heterologous vaccines, of which smallpox and tuberculosis are the only prominent examples). In contrast, most of the vaccine platforms below are manufactured using synthesized genetic material that can be made as soon as the pathogen is sequenced, and no live pathogen is required at any stage in the manufacture process.

(Dead virus is generally referred to as “inactivated virus” to side-step any questions of whether viruses are “really” alive.)

Dead sars-cov-2 vaccines in phase III trials are BBIBP-CorV, developed by Sinopharm, CoronaVac, developed by Sinovac, and BBV152 (Covaxin), developed by Bharat Biotech. The first of these had already been administered to one million people in China by mid-November. (The WHO and others list two different Sinopharm vaccine candidates in phase III, but I can’t find any information that distinguishes them.) A number of other such vaccines have not yet reached phase III trials. None of the attenuated covid-19 vaccine candidates have entered phase I trials yet.

mRNA vaccines

The most important discovery of 20th century biology is where proteins come from. Everywhere we look in the body can be found highly intricate, specialized protein machines. One could even say you “are” your proteins – take out the proteins and you’d be left with bones in greasy, salty sugar water.

So when the body grows or reproduces, one’s mass grows, and new proteins need to be made. However, like almost all chemicals, proteins can’t reproduce, even with the help of the body’s cellular machinery (although see prions). The essential idea behind protein synthesis is that the body makes proteins out of RNA, and makes RNA out of DNA:

\text{DNA} \xrightarrow{\parbox{3cm}{\centering enzymes}} \text{RNA} \xrightarrow{\parbox{3cm}{\centering enzymes}} \text{proteins}

(The above diagram is often, though improperly, referred to as the “Central Dogma”.) As for DNA, it does reproduce in the body. There are a few minor variants on the above scheme, and notably RNA serves many different functions in the body; only a minority of RNA is messenger RNA (mRNA), whose purpose is to be a stepping stone to make proteins as depicted above.

While most living organisms follow the above scheme, the main exception is RNA viruses. Viruses face a unique challenge in how to fit their genome in their capsid shell that larger organisms like bacteria do not have an issue with. Notably, this is why viruses have highly symmetric capsids: the size of a protein is proportional to the size of the gene that encoded it, so viruses make their capsids out of many identical copies of small proteins that can be encoded by short genes.

A glimpse of some of the mathematical concerns that go into understanding the symmetries of virus capsids. For an overview, see the wikipedia article on capsids, and for details see Caspar and Klug 1962. Notice the similarity to soccer ball designs; the mathematics of “tiling” a sphere shows up in many contexts.

RNA viruses take the minimalistic approach of using RNA as a genome, which can be directly translated into proteins. (Although note that the very smallest viruses are ssDNA.) However, the host does not contain enzymes that would reproduce RNA, so RNA viruses must come with the code for making such enzymes. Alternatively, retroviruses such as HIV contain code for enzymes that copy RNA into DNA, which is usually injected into the host’s genome. In theory, if a retrovirus were to infect a germ cell it could be passed on genetically to all of one’s descendants; while this is exceptionally rare, about 5% of the human genome is believed to have arisen from viruses.

Sars-cov-2, the virus that causes covid-19, is an RNA virus. Its genome encodes proteins for reproducing its genome, for its virus capsid, and for other purposes including famously the giant “spike protein” that protrudes from the virus envelope (the fatty layer outside the virus capsid). The spike is used by the virus to bind to human cells, allowing it to enter and reproduce; it is also responsible for the outward appearance of the virus, giving “coronavirus” (crown virus) its name. As the spike is the physically outward most part, it is also the easiest target for the immune system: immune cells need to actually touch the molecules they are reacting to.

The active ingredient of the covid mRNA vaccines is modified mRNA that encodes the sars-cov-2 spike protein. Ordinarily injecting RNA into the body would have little effect, as foreign RNA is typically a sign of viral infection, and the body produces copious RNAses to destroy any ambient RNA. The main challenge of designing an mRNA vaccine is presumably the modifications necessary to evade the body’s defenses against RNA – ironically also the same gauntlet that RNA viruses face. The two leading mRNA vaccine candidates both embed the mRNA in lipid nanoparticles for delivery. They also replace some of the RNA nucleosides with non-standard variants that make it harder for the body to recognize them as being RNA.

If the mRNA successfully gets into the cell and tricks the body into accepting it, then it is translated to make spike proteins. These spike proteins then trigger the immune response in the usual way.

mRNA degrades over time in the body, typically within a few days, after which the production of spike proteins will stop. Neither the body nor the vaccine contains any of the machinery necessary to reproduce RNA or reverse-transcribe it into DNA, so once the mRNA is degraded the vaccine should have no further direct effects; the spike proteins will eventually degrade or be cleaned up by the immune system, leaving only a better adapted immune system behind.

An mRNA vaccine would be equally useful for DNA viruses; it doesn’t matter whether the genes in the vaccine matches the genes in the virus, so long as the proteins they create do match.

There is some possibility that the solid lipid nanoparticles (SLNs) used to carry the mRNA may cause harm. SLNs are a very new technology; they were first approved by the FDA in 2018. The only source I have seen indicating a danger of SLNs is an unsourced 2017 news article claiming that Moderna had problems with them during animal testing of their mRNA treatment of Crigler-Najjar syndrome: apparently repeated doses were harmful, so Moderna pivoted to vaccines where fewer and smaller doses are effective. (Treatment of Crigler-Najjar would require regular doses instead of a one-time cure.) While SLNs are very new, liposomes are a similar drug delivery mechanism that have been in use for many decades; liposomes have a lipid bilayer membrane with the drug contents in suspension inside, instead of solid fat. Liposomes have been used in chemotherapy treatments to carry the toxic chemotherapy drugs into cancer cells, and most papers I saw on liposome toxicity referred to premature release of these chemotherapy drugs. Only one paper I read suggested that certain types of liposomes themselves could be harmful. It is unclear to me if this could apply to SLNs.

The mRNA vaccines in phase III trials are Tozinameran (BNT162b2) developed by BioNTech / Pfizer, mRNA-1273 developed by Moderna. A number of other mRNA vaccine candidates are in phase II or earlier.

DNA vaccines

DNA vaccines work by exactly the same mechanism as mRNA viruses, except that the injected DNA is transcribed to make the mRNA which is then translated to make the spike proteins.

The argument for DNA vaccine safety is less clear-cut than that for mRNA vaccine safety, as the body does contain the cellular machinery to reproduce DNA. Personally I don’t like the idea of foreign DNA being put into my cytoplasm. However, it would be quite hard to get such DNA to replicate deliberately, much less accidentally: without special enzymes like those found in retroviruses, the DNA plasmids can’t be incorporated into the cell’s copy of the genome, and therefore will not be copied by the cell.

The DNA is delivered either as an injection of raw DNA plasmids, possibly with the help of electroporation, or with a gene gun which is a helium gas-propelled gun that shoots gold particles coated in DNA plasmids into the tissue. As the latter inserts the DNA directly into the cytoplasm of the target cells, it can use very low doses.

I speculate that DNA vaccines might have fewer side effects than mRNA vaccines, as lower dosages are possible: DNA is more robust than mRNA, and each DNA plasmid could make many mRNA strands before degrading.

Five of the candidate DNA vaccines have entered phase I or II trials. I believe they use injected DNA plasmids, and at least one uses electroporation.

Non-replicating viral vector vaccines

These vaccines contain a virus which has been modified in some way to make it incapable of reproducing in humans. The virus either has its genome removed or altered in some way; I have had difficulty finding precise details. Additionally, the gene for the sars-cov-2 spike protein is added to the virus, either in the form of DNA or mRNA (some sources have mentioned the use of viral vectors with single-stranded DNA; the AstraZeneca vaccine uses double-stranded DNA). The virus thus delivers this gene into cells; as its own genome is not fully present, it is incapable of causing illness.

In principle this is exactly how the mRNA/DNA vaccines discussed above work, but rather than using lipid nanoparticles to deliver the mRNA, a virus that has evolved specifically for this purpose is used. In practice this may represent a significant difference in safety or effectiveness, as the body might react to the virus quite differently than it reacts to lipid nanoparticles, but I have no specific reason to believe this matters. Phase III trials should reveal if one of these mechanisms is actually better than the other in practice.

The AstraZeneca vaccine uses a chimpanzee adenovirus as its carrier. The reason to use a chimp virus over a human virus is so that humans do not have any existing immunity to the injected virus, which might impair the effectiveness of the vaccine. I wonder if it is possible to develop such an immunity if sufficiently many vaccines were administered that all use this same delivery platform.

One paper I read stated (without sources) that the chimp adenovirus in the AstraZeneca vaccine has the spike protein in its surface, as opposed to merely carrying the gene for making the spike protein in its genome. None of the other sources I read were clear on this point.

Viral vectors have been used since the 1970s, originally for research purposes and later for gene therapy. I am not aware of any use of them for vaccination before covid-19.

There are four non-replicating viral vector vaccines in phase III trials. AZD1222, developed by University of Oxford and AstraZeneca, is the most well known vaccine candidate of this type, and is the one that uses a chimp adenovirus for delivery. Gam-COVID-Vac (Sputnik V), developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia, uses human adenoviruses. I believe that Ad5-nCov, developed by CanSino Biologics in China, and Ad26.COV2.S, developed by Janssen pharmaceutica, use human adenoviruses. Other vaccines of this type are phase I and earlier.

Replicating viral vector vaccines

These vaccines are akin to those using non-replicating viral vectors, except (as one might guess) the modifications to the virus vector do not eliminate its ability to reproduce in the body.

Only one of the replicating viral vector vaccine candidates for covid have entered clinical testing.

Subunit vaccines (raw antigen)

These vaccines involve directly injecting the antigenic molecule. These are called subunit vaccines because the antigen is one piece of the whole pathogen. For sars-cov-2, the only reasonable choice for antigenic molecule is the spike protein. By itself, the spike protein cannot cause any infection, as it is missing the rest of the virus, in particular the virus’s genome.

Such vaccines are generally manufactured by creating recombinant cells (usually bacteria, but sometimes yeast, insect, or mammal) which contain the gene for the spike protein. These cells are grown and harvested, and then the spike protein is purified from the result.

(In theory these vaccines could be manufactured by growing the pathogen directly; in this case, conceivably improper purification and sterilization could result in a vaccine accidentally causing the disease. However I’m not aware of any vaccines made this way, and sterilization can be done very reliably.)

NVX-Cov2373, by Novavax, is a protein subunit vaccine in phase III trials. Various sources describe a protein subunit vaccine by Anhui Zhifei Longcom Biopharmaceutical as in phase II or III. There are an additional 9 such candidates in phase I or II and 65 vaccine candidates not yet in clinical trials.

Live recombinant bacterial vector vaccines

These vaccines involve the creation of recombinant bacteria, as described in the previous section, which produce the spike protein or other antigen. Instead of purifying the spike protein, the bacteria are directly injected into the body. Depending on choice of bacterial vector it may be possible for the vector itself to cause infection; but in this case antibiotic can be administered to treat it.

I am not aware of any working vaccines of this type, whether for covid or other diseases. However there have been proposals to use recombinant BCG as a vector. Live non-recombinant BCG is used as a vaccine for tuberculosis, as the two bacteria are closely related, but the former only rarely causes disease in healthy individuals.

There are two candidate covid vaccines of this type; neither have reached clinical testing.

Virus-like-particle vaccines

Vaccines containing VLPs (virus-like particles) are like subunit vaccines, except that the subunit is most of the virus; for example, it could be the whole virus capsid. As virus capsids readily self-assemble, these are generally manufactured by “just” making each of the subunits that are in the capsid and mixing them. VLPs do not include the genome and possibly other key components of the virus (such as RNA polymerase for negative-sense RNA viruses) so that no infection occurs.

Manufacture of VLPs for enveloped viruses like sars-cov-2 is somewhat harder as the envelope generally needs to be made by budding from a host cell, as in a live infection. (No capsid would be included in enveloped VLPs.) Eukaryotic hosts are generally required to make enveloped VLPs, which are harder to work with than bacterial hosts.

CoVLP by Medicago Inc. is a VLP vaccine that involves recombinant bacteria living in plants; I believe the bacteria produce the envelope proteins while the plant cells perform the budding to create the VLPs. Sources variously list it in phase III or I trials. A vaccine by SpyBiotech and the Serum Institute of India appears to be in phase I-II trials. Other VLP vaccine candidates are pre-clinical.

Toxoid vaccines

For pathogens that create harm through the release of a toxin, toxoid vaccines train the immune system on that toxin rather than on the pathogen. Such vaccines contain “toxoids” that are chemically similar to the toxin without being toxic themselves. Tetanus, diphtheria, and pertussis are vaccinated this way; this platform cannot be used to protect from covid-19.

A note on “recombinant vaccines”

A number of vaccine candidates I examined were described as “recombinant vaccines”; I had some difficulty understanding exactly what was meant by this label. I believe it can be used to describe any vaccine for which the creation of recombinant organisms (cells or viruses that contain genes naturally found in different source organisms) is one of the steps of the manufacture, not just for vaccines where such recombinant organisms are in the vaccine itself. Because recombinant bacteria (or other “expression hosts”) are broadly used for cheap protein production, they form one of the early steps in the manufacture of most vaccines described above that use the viral vector, subunit, or VLP platforms. Recombinant bacteria have many applications in pharmaceuticals, notably for large-scale insulin production.

Discussion

Particular dangers of the covid vaccine

First, we can dispense with the question of whether the vaccines can cause covid-19. Only the vaccines of dead or attenuated virus involve any actual sars-cov-2 virus at any stage in their manufacture; the other vaccines are missing essential components of the virus, such as RNA polymerase, and are absolutely incapable of causing covid-19.

The safety of vaccination with dead or attenuated virus depends on trusting the reliability of the processes that kill or weaken them. Illness caused by such a vaccine is exceptionally rare: reversion of attenuated poliovirus causes polio in about 1 in 5 million children receiving the attenuated vaccine, but I am otherwise unaware of any cases of reversion in dead or attenuated vaccines of any disease. “The cold-adapted influenza vaccine […] has never reverted to virulence in a vaccinee.” (source) The MMR / MMRV vaccine is an attenuated vaccine given to 85% of children worldwide before the age of one. Some attenuated vaccines may be unsuitable for severely immuno-compromised individuals.

Due to the theoretical potential of a dead or attenuated vaccine to cause disease, I would personally reject an attenuated covid vaccine if one existed for me to reject, and would prefer another covid vaccine platform over a dead sars-cov-2 vaccine. This only applies to novel dead and attenuated vaccines, and the attenuated polio vaccine, as other established dead and attenuated vaccines have thoroughly demonstrated their safety.

The immune system’s reaction to the antigen, which is the purpose of the vaccine, may itself be dangerous to individuals with severe immune system problems; this is not specific to covid vaccination, or the platform by which the antigen is delivered. For a healthy person, the immune system’s reaction will be to develop some degree (possibly none) of immunity to sars-cov-2. Generally speaking one would expect there to be no downside to this; however, dengue virus is believed to exhibit antibody-dependent enhancement, wherein exposure to dengue virus increases the severity of disease when exposed to a different strain of dengue in the future. I am not aware of any credible reason to think this could happen with sars-cov-2, and if it did, it would have been likely to be noticed in phase III trials.

General dangers of the covid vaccine

Having considered the dangers of the active component of the covid vaccines, this leaves us with the more ordinary components. There are many variations from one vaccine to another, and even if I knew all of their ingredients I lack the highly specialized knowledge to evaluate them in detail, so I am forced to speak more broadly. Generally speaking there are three such categories: adjuvants, which amplify the immune response and allow lower dosages to be effective; stabilizers, which slow the decay of the active ingredients and protect against biological contamination; and the delivery platform itself, as described above. For each such chemical that appears in a covid vaccine that is accepted by western regulatory bodies,

The exception is the novel vaccine platforms which may violate point 3 above, so let us discuss this a little further, by considering each relevant platform.

It seems to me that, having examined the safety of each aspect of the vaccines, any plausible means by which they could cause grave harm to healthy recipients has been eliminated. That leaves us with the unknown unknowns, the risk factors that we can not reasonably anticipate. We can conjure an endless list of these possibilities: perhaps a large number of people were involved in cheating on the clinical trials; perhaps there is some additional biological function to mRNA yet undiscovered; perhaps moving to industrial-scale vaccine production will result in the introduction of some toxic contaminant. If some unknown unknown turns out to be dangerous, it is (by definition) going to be one we couldn’t predict, so we need to assess these risks collectively.

A helpful point of comparison for these unknown unknowns is the food we eat. There are all sorts of chemicals we are ignorant of in our food, whether they are added in industrial processing or synthesized in the natural growth of the food or absorbed incidentally from the soil it grew in. Yet, we don’t worry about whether micrograms of some mysterious substance in our food will conceal itself in our body to come out and harm us years later.

I believe that any means by which the covid vaccine could unexpectedly cause danger to a recipient in spite of the thorough testing and regulatory oversight would apply even moreso to the food industry.

Final thoughts

For an American who is not in a strictly isolating quarantine circle and does not have any particular health conditions that preclude them from receiving vaccinations, I judge the insignificant and unknowable dangers of the covid vaccine to be lower than the alternative of no vaccination. For those in strict isolation or who live in countries (such as parts of east Asia) where there no community spread, if there is a vaccine shortage or rationing you may get more benefit by letting others receive theirs earlier.

xkcd.com/2397

We are very lucky that a safe and effective vaccine is or will soon be available. The first vaccine was risky and deeply unpleasant. And yet vaccination was so much better than having no immunity at all that people went to enormous lengths to perform it:

In 1803, the king, convinced of the benefits of the vaccine, ordered his personal physician Francis Xavier de Balmis, to deliver it to the Spanish dominions in North and South America. To maintain the vaccine in an available state during the voyage, the physician recruited 22 young boys who had never had cowpox or smallpox before, aged three to nine years, from the orphanages of Spain. During the trip across the Atlantic, de Balmis vaccinated the orphans in a living chain. Two children were vaccinated immediately before departure, and when cowpox pustules had appeared on their arms, material from these lesions was used to vaccinate two more children.

FAQ

If the vaccine can’t give you covid, why I have heard about people becoming ill after receiving the vaccine? Mild fever and other symptoms are part of the immune system’s reaction to the vaccine. The mRNA covid vaccine in use in the US is absolutely totally incapable of causing covid. Of course, it is possible to be exposed to covid or other illnesses around the same time as receiving the vaccine, so do not ignore any serious health concerns.

Does the vaccine prevent you from carrying sars-cov-2 and infecting others? If you are immune to sars-cov-2, you cannot develop or transmit the infection. Whether the vaccine grants you this immunity may vary on the vaccine and from person to person; it is certainly possible that the vaccine could reduce the severity of illness without producing full immunity. The extent to which this actually happens should be measured in phase III trials.

Is it possible to measure whether the vaccine gave me immunity? Blood tests can measure the presence of antibodies, which are generally indicative of a previous immune reaction, whether caused by a covid infection or the vaccine. These antibodies give an incomplete picture of the body’s immunity, and measurements have a high error rate. I am not aware of any better way of testing for immunity.

Does the vaccine continue to protect even if sars-cov-2 mutates? Antigenic drift refers to mutations in viruses that affect the part of a virus you develop immunity to. Strong antigenic drift in flu viruses cause new vaccines to be produced and administered each year. However, “diversity among influenza A surface glycoproteins is 437-fold greater than that measured in SARS-CoV-2”. Hopefully the lower diversity in sars-cov-2 mutations means that one vaccine provides good immunity to all existing strains.

How long does immunity from the vaccine last? We don’t know.

I have medical condition X, can I get vaccinated? Ask a doctor.

Can the same technology be used to create a vaccine to some/all strains of the common cold? Actually I haven’t heard others asking this – this is my question and I want to know!

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