Assorted Topics Regarding Viruses and Vaccines
With flu season in full swing, I thought it was time to get back to this blog’s original purpose. I’ve had a running list of smaller topics related to viruses and vaccines that are worth talking about but are not long enough for a full post in-and-of themselves. Now that I’ve accumulated enough topics, I can share them. And with good quality, factual information about vaccination becoming harder to acquire, I believe I have a duty to talk about this. So without further ado…
Oncoviruses and Carcinogenic Infections
You may be familiar with the concept that some viral infections, such as HPV, Epstein-Barr, or Hepatitis, are linked with higher risks of developing cancer. In fact, recent research suggests that one-in-eight cancers worldwide may be at least partially caused by viruses and other infectious agents. The exact details of the mechanisms these infectious agents use to cause cancer is still being researched, but the broad strokes are understood fairly well.
Direct Oncogenesis
Direct oncogenesis is when the infectious agent itself causes cells to mutate as part of its reproductive strategy. This is only seen in viruses that cause persistent infections. All viruses reproduce by inserting their genetic material into a cell, using the DNA replication and protein constructing mechanisms of the cell to produce thousands of copies of the virus, then killing the cell to let the new viruses escape. But some viruses¹ are capable of viral integration, meaning they have additional mechanisms that let them permanently incorporate their genetic material into the cell’s genome and regulate it in response to its environment. This means that instead of immediately killing the infected cell, the virus can lay dormant indefinitely until the perfect opportunity to infect other cells comes along. This is why viruses like HIV/AIDS and herpes are still not yet curable; the viruses will lie dormant in their infected cells (which from the outside still looks perfectly normal) until whatever drug or immune response that’s hurting them passes. It's also why shingles exists; the chickenpox virus can lay dormant in the body until the immune system weakens with age. And since these viruses are manipulating their host’s genome to their benefit, they can change the cell’s behavior if doing so helps them. Many integrating viruses will make their host cells reproduce faster in order to produce more infected cells, and will disable certain mechanisms of DNA repair that might allow the cell to resist the hijacking. And when cells begin reproducing more rapidly and can’t repair their DNA, the mutations that cause cancer become more and more likely. These infected cells becoming cancerous is technically to their benefit since it means faster reproduction, so there’s no reason for the virus to prevent carcinogenesis. Examples of viruses that cause these types of infections include Epstein-Barr (mono), Hepatitis B, and HPV.
Since human papillomavirus (HPV) is perhaps the most well-known oncovirus, I’ll give it a bit of a deep dive. A predominantly sexually transmitted infection (90% of cases), the most common sites of infection are the cervix, vulva, vagina, penis, anus, mouth, tonsils, and throat. Despite being able to integrate its genetic material into a host cell, HPV doesn’t have to do this to infect a cell, only doing so in 10% of cases. The 90% of HPV infections that don’t integrate themselves end in less than two years with all viruses cleared from the body (the infection lasts this long because HPV is very good at hiding itself from the immune system). Warts can occur in these cases as the virus causes increased cell growth, but these stop recurring once the virus is cleared from the body. But if it's a particular strain of the virus (there are over 200 strains of HPV), the immune system is slow to respond (such as if the patient is older or has a weaker immune system), or if the number of viruses in the body are higher (such as if the patient is infected multiple times in succession), those odds might bend in the virus’ favor. Once a persistent infection begins, the virus deliberately interferes with critical DNA repair proteins such as p53 and pRb. In 10% of persistent HPV infections, cancer develops in the infected tissue. While 10% of 10% isn’t a lot, 85% of people contract HPV during their lifetime, so this translates to roughly 40,000 cases of HPV-related cancer per year in the United States alone.
Indirect Oncogenesis
Another mechanism is indirect oncogenesis which occurs when an infectious agent causes chronic inflammation or otherwise damages infected tissue in such a way that promotes carcinogenesis. Inflammation can damage DNA when it is done chronically, and the constant cell replication needed to repair damaged tissue gives more opportunities for harmful mutations. This can be done by any infectious agent that causes long-term infection, viral or bacterial. Examples of such diseases include Hepatitis C and HIV, but I’ll focus on Helicobacter pylori, a common bacteria that infects the lining of the stomach. H. pylori is contracted via contaminated food or water or through direct exchange of saliva or fecal matter. Roughly two-thirds of the human population is believed to have some form of H. pylori infection, with most of those infected being in low-to-medium income countries. Once in the stomach, the bacteria embeds itself in the stomach lining to protect itself from the acidic environment of the stomach. Since the immune system can’t effectively reach the bacteria, the infection can persist indefinitely or be lifelong. Only 10-20% of those infected will have symptoms (due to the strain of the bacteria, the strength of the immune response, and certain dietary and environmental effects), but those unlucky few will experience chronic inflammation of the stomach lining, causing gastroenterological problems and peptic ulcers. Those infections that cause symptoms are often caused by H. pylori strains that produce CagA, a toxin that damages the cells of the stomach lining so they spill their nutrients for the bacteria to steal. Between the DNA damage caused by the chronic inflammation and CagA, many with symptomatic H. pylori infections will develop stomach cancers. Many of these stomach cancers are exclusively seen in those with H. pylori infections.
Cancer is just one way that a viral infection can cause long-term health effects. Other examples include post-viral syndrome (such as long covid), and immune amnesia (when a disease, such as measles, infects and destroys T- and B-cells, undoing a patient's immunity to past infections and making them more vulnerable to infection for years to come). “Natural immunity” which has been touted of late as a more natural way to prevent infection, is in no way safer than vaccination. The good news is that if an eighth of all cancers are caused by infections, then an eighth of all cancers are extremely preventable. With improved sanitation and antibiotic access throughout the developing world, cases of H. pylori and their associated cancers have been in decline globally. HPV rates have been in decline as well due to the extremely effective vaccine against it. Hepatitis B also has an effective vaccine and there is research being done on vaccines against Epstein-Barr and Hepatitis C. Vaccination lowers your odds for both the short and long term effects of these viruses.
Sterilizing vs Functional Immunity
I’m sure at some point since the pandemic, you’ve had the question “why doesn’t the Covid-19 vaccine make you completely immune to Covid?” We’ve all been taught that vaccines make you totally immune to the viruses they target, but we all know people who were vaccinated but still got Covid. And to be clear here, the Covid vaccine does give you functional immunity, meaning your immune system can recognize the virus and prevent severe symptoms. Being vaccinated means that what could’ve been a light case of Covid won’t cause symptoms, what could’ve been a case that hospitalizes you won’t, and, maybe most importantly for community health, you will be far less likely to transmit the virus to others. Getting vaccinated absolutely makes you far better off than not doing so. But why do none of the Covid vaccines give you sterilizing immunity, meaning the virus can always kill off the virus before it begins to replicate in your body and symptoms begin?
The biggest factor in sterilizing immunity is the development of long-lived plasma cells. As I’ve mentioned before, antibodies are proteins secreted by immune cells that bind to a specific antigen on the surface of a virus, thus disabling it. Your lymph nodes produce billions of naive B-cells each day, each capable of producing unique antibodies. When a new pathogen enters the body, the immune system finds one of the billions of naive B-cells whose antibodies just so happen to bind to the pathogen. Once this one-in-a-billion cell is found, it reproduces rapidly and matures into several new cell types; particularly short-lived plasma cells and memory B-cells. Plasma cells will flood the bloodstream with antibodies, killing off the infection. Once the infection is cleared, memory B-cells will continue to reside in the lymph nodes and circulate through the bloodstream, ready to begin mass production of antibodies the moment their pathogen is detected again. Short-lived plasma cells will migrate to the bone marrow, one of the most well-protected parts of the body, and will continuously produce antibodies for anywhere between a few days to six months. After this period, they will either die off or turn into long-lasting plasma cells (LLPCs). LLPCs will produce antibodies continuously for the rest of your life, which can prevent any infection severe enough to cause symptoms.
But not all diseases trigger the formation of LLPCs, and coronavirus infections rarely if ever produce LLPCs. There are a few reasons for this, but they all revolve around a common issue; triage. A continuous production of antibodies is very resource intensive, so your body won’t do it unless it makes perfect sense to. The exact mechanisms by which your immune system decides what diseases warrant an LLPC defense is still being studied, but the features of coronaviruses that make them less likely to warrant this defense include:
Location. Diseases that are most likely to trigger LLPC defenses are those that get into the blood stream and spread quickly throughout the body, such as measles, Epstein-Barr, and chickenpox. Since coronavirus infection is limited to the upper respiratory tract (nose to the larynx), and very occasionally the lower respiratory tract (trachea down to the lungs), the immune system doesn’t get the same intensity of signals that would convince the immune system that this virus is a threat worthy of LLPCs. Additionally, because LLPCs are confined to the bone marrow, their antibodies are unable to leave the bloodstream. This makes LLPCs less effective against infections in the respiratory tract (especially the upper respiratory tract), and thus less worth making.
Mutability. As I’ve mentioned before, Coronaviruses are one of the fastest-mutating clades of viruses there is, similar to flu. This is why you have to get vaccinated against flu and Covid every year; the virus changes so much in one year that last year’s immune response won’t be effective against this year’s strain. So the immune system rarely produces LLPCs for coronavirus infections; it doesn’t want to spend a lifetime generating antibodies that won’t be effective in a year. Viruses that mutate and change slowly, such as measles, mumps and rubella, frequently do produce LLPC responses.
Defenses. Like many viruses, coronaviruses have evolved multiple means of defending against the immune system. Among these defenses is the ability to make infected cells secrete proteins that downregulate the immune system, essentially muffling the body’s warning system. Since this makes Covid look like a less deadly infection, LLPCs don’t look to be necessary. (This could only occur during a coronavirus infection, so this is less of a factor in the lack of LLPC response to Covid vaccination.)
Similarity to other Coronaviruses. This is a very new hypothesis that is not yet fully developed or accepted, but I thought it was interesting enough to mention. The hypothesis goes that because coronaviruses are so common but are only a minor nuisance in the vast majority of cases (they make up 15% of cases of the common cold), the immune system has evolved to tolerate them and not regard them as major threats. Your immune system does not have the resources to create an LLPC response for every coronavirus it encounters, and the vast majority of these coronaviruses are fairly harmless. Part of what makes SARS, MERS, and Covid-19 so dangerous might be that your immune system stereotypes them as benign. How the immune system can recognize that an antibody response is against a coronavirus is still being studied.
Just because an infection doesn’t produce LLPCs doesn’t mean you’re defenseless. Regardless of LLPC production, all infections will prompt the creation of memory B-cells (as well as other acquired immune cells like T-cells). While LLPCs constantly produce a low level of antibodies, memory B-cells produce a high level of antibodies and can turn this production on and off. When a person is exposed to Covid-19 for the second time (whether the first time was by infection or immunization), B-cells circulating through the bloodstream will eventually find the infection and will start mass producing antibodies to stop them (along with other immune cells). You might have symptoms because the immune defense can’t start until after the infection has been detected, at which point it could have already spread and caused some damage. But the existing antibody and T-cell response means that the immune system can begin fighting back much faster and more effectively than it could during the first exposure (via infection or immunization), so symptoms are far milder and shorter-lasting than they otherwise would be. An LLPC response would mean that there are antibodies against the disease in the bloodstream at all times. An infection would be on the backfoot from the moment it entered the body, so symptoms likely wouldn’t start before B- and T-cells could find the infection and finish the job.
Finding ways to make the antibody responses to Covid-19 last longer has been a topic of research since the pandemic began. As it stands, the circulating antibodies produced by the Covid vaccine begin to fade after six months, as the vaccine only produces short-lived plasma cells. Again, production will ramp right back up if you are infected again, but that gap in production might leave enough room for a few symptoms. We know that more severe infections will produce longer-lasting immune responses and make LLPC responses more likely, but that doesn’t really help us when our goal is preventing disease. Telling our immune systems to produce LLPCs is currently beyond us, and it probably wouldn’t be worth doing in Covid’s case since the lifetime immune response would be rendered useless in a year. Fortunately, the mutability of Covid kind of works in our favor here; since you have to get vaccinated against the newest strains every year, there won’t be too much time where you do not have the strongest antibody defense. So, remember to work with your immune system and get vaccinated for Covid and flu every year.
mRNA Versus Protein-Based Vaccines
You may have seen recent advertising for a non-mRNA vaccine against Covid-19. Nuvaxovid is a protein-based vaccine, meaning it’s made from Covid spike proteins grown in culture and then mounted onto nanoparticles so they resemble a real virus. The vaccine has been available in a limited fashion since 2022 under an emergency use authorization, but has had full FDA approval since 2025. While I would normally consider this a good thing and probably not worth writing about, I’ve seen some advertisements for this vaccine that seems to suggest that it causes fewer side effects than mRNA vaccines. This appears to be based on a single study² and I worry this messaging could be read as saying that being protein-based makes it safer than the mRNA vaccines against Covid. So, despite having talked about this before, I feel a need to defend mRNA vaccines.
When one of your cells is infected by a virus, it does have ways of resisting. One such way is to take viral proteins being manufactured inside themselves and mount them on their surface, while sending out signal proteins saying they’ve been infected. Certain innate immune cells (the first responders to a new infection) called dendritic cells will notice these signal proteins and come investigate. The dendritic cells will take the viral proteins from the body cells and mount them on their own surface. They will then travel to the lymph nodes to find T- and B-cells that happen to respond to these antigens. The T- and B-cells that do respond reproduce rapidly and mature into the cells that give you a permanent immune response to that pathogen. Dendritic cells can also “eat” viruses they find outside the cells, digest, and mount undigested viral proteins on their surfaces that way. Traditional vaccines work by replacing the healthy, dangerous pathogen with a non-deadly version (a weakened virus, loose viral proteins, or the aforementioned nanoparticles coated in proteins) and a chemical adjuvant that tricks the immune system into thinking this fake infection is a real threat. Dendritic cells believe these weakened viruses are a threat, eat them, and use their proteins to start an immune response. mRNA vaccines replace these viral proteins with the genetic information needed to make them wrapped in a bubble of lipids. Body cells absorb these bubbles, use the mRNAs as instructions to manufacture the antigen proteins, and then “believe” they’ve been infected because of adjuvants in the bubble. The body cells raise the alarm to call dendritic cells (despite there being no real danger) and mount the newly built Covid proteins on their surfaces. Dendritic cells respond to the threat and collect these proteins as they would normally.
Because body cells are actively engaged in the immune response, there’s evidence the immune system takes mRNA vaccines more seriously and thus leads to stronger immune responses. Because there is no “living” pathogen, there are no safety concerns of accidental infection³. Manufacturing mRNA vaccines is far faster and easier than traditional vaccines as it only requires the identification of an antigen and the synthesis of viral mRNAs. It is partly because of this ease of manufacturing that it took only 11 months for the first mRNA Covid vaccines to receive preliminary emergency use authorization; scientists knew in January 2020 which Covid protein would be the perfect antigen and could design the vaccine in a matter of days. Making vaccines the traditional way requires culturing viruses, which can take weeks of industrial scale cultivation, and often breeding new strains which takes a lot of trial and error, and this is all before clinical trials.
The biggest disadvantage to mRNA vaccines is that they aren’t as shelf-stable as traditional vaccines (thus needing to be stored at colder temperatures), and there might be some unique side effects (though this is still being studied). Aside from that, mRNA vaccines are a major boon for medicine with ongoing research into other applications for the technology, with research into possible vaccines against flu, lyme disease, and HIV as well as potential uses for cancer immunotherapy. And this isn’t a new technology; the first lab tests of mRNA vaccines on mice were done in 1989 and the first human clinical trials were done in 2013. A big reason why we didn’t see commercial use of mRNA vaccines before the pandemic is simply because medical regulators are understandably quite risk-averse. Drugs that are based on novel technologies, even if they have the potential to be far better, are less likely to get approval by state regulators like the FDA if there is a tried-and-true treatment that works perfectly well. The unique regulatory environment⁴ that existed during the pandemic gave novel treatments like mRNA vaccination the opportunity to prove themselves, and we can now benefit from this now-proven technology.
And of course, one bit of important mythbusting. There is no risk whatsoever of an mRNA vaccine altering a person’s DNA. As I’ve discussed before, DNA and RNA are two very different molecules with very different uses. DNA is extremely long-lived, making it perfect for information storage, while RNA breaks down in a few hours, making it perfect for moving information from place to place. If DNA is a library-bound book, RNA is cheap scratch paper. All the instructions for making every protein in your body are kept as strands of DNA, safely tucked away inside your cell’s nucleus away from anything in the cell that might damage it. When a cell wants to make a protein, the instructions are copied as a strand of mRNA which is sent to machinery outside the nucleus to make the protein. There is no way for a human cell to turn RNA back into DNA, much less incorporate it back into your genome.
I don’t want to make it sound like I’m criticizing the new vaccine or its manufacturers. Any vaccine that has been approved by the FDA is a good vaccine, and if Nuvaxovid makes someone who’s scared of mRNA vaccines comfortable enough to get vaccinated, then that is technically a net positive. But I also don’t want anyone or anything to convince you or anyone else that mRNA vaccine technology is in any way more dangerous than traditional vaccination. This is a technology that has more than proven itself.
One More Cool Thing
As a closer, I wanted to show you something. Recently, the Youtube channel Kurzgesagt released a video about the use of viruses (specifically viruses bred for vaccine use) to treat cancer. Specifically, the self- experimentation of Dr. Beata Halassy who used her own expertise in virology to treat her own breast cancer. This video almost made me want to do a post about this topic, but there’s no way I’d be able to do it better than the original. So consider this my first media recommendation, both for this topic in particular and for Kurzgesagt in general.
For More Details
¹ You may or may not have heard these viruses referred to as retroviruses, but that’s a little bit misleading. Retroviruses are a specific clade of viruses and every virus in this clade (such as HIV) causes persistent infections. But there are viruses outside this clade that can also cause persistent infections, such as HPV, herpes, hepatitis, and Epstein-Barr. All retroviruses are integrating viruses, but not all integrating viruses are retroviruses.
² As I’ve said before, one study is not enough to say something is definitely true. You need multiple studies saying the same thing before you can reliably say something is true, and there are other studies saying the side effects of Nuvaxovid are comparable to mRNA vaccines. I don’t mean this to be a harsh criticism of Nuvaxovid’s manufacturer (Novavax) as using single studies as part of a drug’s advertising is an unfortunately common practice.
³ Attenuated vaccines (those made from a living virus that has been bred or altered to be less virulent) do carry some risk of infecting the patient with the genuine article. This risk is very slight, and those most at risk are those that are immunocompromised, who are usually not eligible for the vaccine for this reason. I mention this risk solely so I can say it’s not zero while that of mRNA vaccines is zero.
⁴ As I’ve said before, this is not to say there was no drug regulation for the Covid vaccine or that they are less safe due to the rush. There are plenty of ways to accelerate drug development without compromising safety, such as letting Covid vaccines “skip the line” for getting their data assessed by regulators or taking the financial risk of running clinical trials in parallel. If you’ve ever heard the phrase “good, fast, cheap - pick two,” well the United States alone spent ~$32 billion on Covid research during the pandemic.
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