Coronavirus news & views

While SARS-CoV-2 And Our Immune Systems Do A Dance, We Get Re-Infected

Note: Artificial intelligence wrote nary a word of the following article, which was fully composed by the natural intelligence of a certain human.

Your sometimes humble blogger remembers how immunology science first beguiled him. It was during senior year in high school in the Virginia suburbs of Washington, DC. More specifically it was during a lunch break while working at a People’s Drug Store that had a lunch counter. Your then nascent blogger grabbed the recent issue of Scientific American from the magazine rack and opened it to an article that was way above his green scientific understanding but, he, nevertheless, gleaned from the article that the immune system could make antibodies to just about any molecule in the universe, even ones newly created in a lab that the universe had never seen. Amazing!

Your immune system would also make antibodies against the cells and tissues of your best friend and everyone else in the world, and vice versa, but you and your best friend, et al., would not make antibodies against the same cells and molecules in your own bodies! What?

“Holy cow!” I thought. How in the world can the immune system do all that? How can it respond to something the world had never seen and secern friend from foe? At that moment, at that lunch counter over a burger, Coke and an article I barely understood, an immunologist was made. And I did indeed go on to earn a PhD in immunology and I indeed have studied how the immune system recognizes viruses and have done vaccine research. What a pivotal lunch break that was for me.

The question about antibody discrimination clearly fascinated me. That mystery has been solved and a few Nobel prizes awarded for its elegant solution, but related spin-off questions about how antibodies protect us keep coming up in different ways. It did so most recently during the COVID pandemic. Why weren’t the antibodies we generated via vaccination or via natural infection more protective against subsequent infection? In a twist in the plot of biology, it turns out that we have learned that the answers to these questions center around a complicated dance performed between both the virus and immune biological systems.

Biology is so doggone interesting!!

COVID Vaccine generated immunity: The several vaccines we now have against the SARS-CoV-2 virus are effective and provide examples of how vaccines are very good at getting the immune system to respond to what it detects as foreign invaders. But the vaccines are just designed to tell our immune systems to make antibodies against just a very small fragment of the spike protein. In contrast, the virus is constructed of several large proteins each of which has many different regions that the immune system can separately recognize as foreign. In other words, if the virus is like a brick building, your system theoretically can make a different antibody that specifically recognizes each brick of the building. So, the vaccine is like exposing the immune system to about 2-3 bricks of the whole building and trusting the resulting immune response against those few bricks to bring the whole building down.

The immune system was very good in generating antibodies to a small portion of the virus, yet many vaccinated people still were infected and caught COVID. Does that mean, as many vax naysayers claim that the vaccines were ineffective? Not at all, as I have discussed here before. While the CoV-2 vaccines did a good job at protecting against serious disease and death they were not very good at preventing the spread of the virus. These vaccines effectively generated a systemic immune response, meaning that you had anti-viral antibodies circulating in your blood, which did do a very good job preventing serious disease once the virus got inside you. But, it still got inside. You still got infected and got mildly sick.

We now know that the virus enters via mucous membranes in your nose, sinuses, mouth, throat and eyes. It has to first cross mucous membranes in order to infect you and that is where it needs to be stopped in order to actually prevent infection and further spread to others. The problem is that mucosal immunity is caused by a different type of antibody than what circulates in the blood and by what is generated by a typical vaccine that is given by an injection in the arm. To generate mucosal immunity, you need a vaccine that you spray in your mouth or nose, which then should generate the type of antibodies that provide mucosal protection and better protect you from infection via that route and better prevent the virus from spreading through a population.

At the beginning of the pandemic, we were faced with a brand new pathogen for which we knew nothing about how it behaved or how it infected and spread between people. At that point, we reasonably chose to quickly make the most common type of vaccine--a shot. While it didn’t fully protect against getting infected, it nevertheless was very effective at protecting against serious disease. So, it did a good job. Current efforts are underway to develop a mucosal vaccine. But, we must also deal with other complications we have learned about the dance between the virus and the immune system to make sure that vaccine will be maximally effective at preventing infection. Read on.

“Natural” COVID immunity: As it became clear that vaccinated people were still getting infected, the vaccine dissenters and dissemblers proclaimed loudly, and still do, that the vaxes failed miserably. They ignored the survival data and only focused on the infection data. They then began touting “natural immunity,” which is the immunity one usually gains after being naturally infected. But, that can be uncertain given the fact that the route of infection and the dose of virus can vary wildly and confer different levels of protection, as I reported earlier. Plus, with natural infection, one runs the risk of serious disease and death from the disease.

Then, to the chagrin of the “natural immunity” enthusiasts it turned out that they also were getting re-infected! And this re-infection occurs despite the fact that natural immunity occurs after infection across the mucous membranes that should, as discussed above, generate an immune response that would stop an infection! This is the dance.

Therefore, we now know that neither vaccine immunity, nor infection immunity fully protects against future infection with the CoV-2 virus (there is partial protection, but I won’t go into that here).

As we learned as recently as last April, from a Harvard study published in the journal Science, despite the fact that a natural infection presents the immune system with the full viral “building and all its bricks” potentially recognizable by antibodies, it turns out that only a few of the “bricks” are in fact actively “seen” at any time by the immune system.

This immuno-dominance of a small part of a larger pathogen that has thousands of sites or bricks the immune system can recognize is not unusual. It is like a large building consisting of thousands of bricks, but having a very attractive window that draws your attention. While you know an entire building is there, your attention is mostly drawn to the window. So can the focus of the immune system be preferentially drawn to a small part of a larger edifice. The immune system is perfectly capable of seeing the rest of the “building,” but it prefers to direct its attention to a small part of it. However, if you take away the part it prefers to focus on, the immune system will easily recognize something else. This immuno-dominance in what the immune system “sees” has several causes that are way too complicated to go into here without writing a textbook (an interested reader might try Paul’s Fundamental Immunology. My rather old edition of that book runs about 1500 pages!). Suffice it to just know that this sort of immuno-dominance often happens where only a small part of a large pathogen is preferentially recognized by the immune system.

Thus, the immunity developed after a natural infection is mostly only directed at a small portion of the virus, much like the antibody response after vaccination with just a small part of the virus. The natural immune response, like the vaccine immune response, is robust and effective, yet both are only directed against a very small portion of a big pathogen, and both are very leaky in that one can still get infected again! What gives?

Mutation gives.

How the virus escapes immunity: The SARS-CoV-2 virus is highly mutable unlike the other viruses like polio and small pox we vaccinate against and maintain long term immunity against. Thus, the virus quickly mutated, or changed, the “bricks” against which the vaccines were made rendering the immune response less and less effective over time as new viral iterations appeared. That is why the many boosters we got were necessary to keep vaccination immunity up with viral changes.

And that also is how someone who became immune after natural infection also became re-infected. The virus did a two-step and mutated the small region recognized by the immune system. It was pretty easy for the virus to do since it only had to change a couple of “bricks” in its facade that the antibodies were mostly attacking. That means that upon re-infection with a slightly mutated virus, the immune systems have to be re-educated to recognize a new intruder, and that takes time, which allows a new infection to settle in. Thus, in this dance, the gentleman virus leads and the dame immune system follows.

New vaccines continue to be developed that scientists hope will solve these problems unique to SARS-CoV-2. Most of the new vaccines are being built on the mRNA platform, but using novel approaches to 1) develop vaccines that can be given as a nasal spray in order to generate the mucosal immunity that hopefully would be more effective at actually preventing COVID. If this works, it might even be possible to hinder COVID spread. 2) But in order to block CoV-2 spread on a population level, we need to find other regions of the virus that are not so highly mutable. These would conceivably be regions of COVID proteins critical for viral function that tolerate little change in structure because that change would destroy the proteins' critical function and essentially kill the virus. Alternatively, new vaccines could incorporate multiple "bricksl" from different regions of the edifice assuming that it would be nigh impossible for all those sites to simultaneously mutate. If such regions are accessible to the immune system, then the resulting immunity would be expected to be impervious to viral mutation, thus ending the dance on a sour note.

It is even possible that such a vaccine could protect against a wide range of coronaviruses, thereby preventing future health problems arising from new coronaviruses. Remember SARS that also popped up in China a couple of decades ago? That virus has some genome similarity to the virus that caused the COVID pandemic, and both are distantly related to the virus that caused MERS that arose in the Middle East. If a pan-coronavirus vaccine can be developed, it could feasibly prevent many future epidemics and pandemics.

We shall see.

This is all part of a new biology that I earlier dubbed BioX. Biology is so doggone interesting!!

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The History Of Vaccine Mandates In The US

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As employers and the President are pushing vaccine mandates because too many have refused them, voices are crying out for their perceived rights saying “my body my choice.” They do not like their bosses or the government telling them to get vaccinated. This is a clash between individual rights and public health measures designed to save lives and to protect the larger community. Who gets to make the key decisions? How far can the government and employers go? Do individual rights trump community safety?

On Sept. 9, Biden announced the most sweeping vaccine requirements in American history, ordering that businesses with 100 or more employees ensure that all their workers are either vaccinated or get tested weekly for the coronavirus. The new rules also require vaccinations for federal workers and for federal contractors, as well as for workers at healthcare facilities that receive funding from Medicare and Medicaid. This will affect about 100 million people.

The authority for these government mandates, claims Biden, is a 1970 federal statute that gives the Secretary of Labor authority to issue a six month Emergency Temporary Standard (ETS) to protect workers from “grave danger from exposure to substances or agents determined to be toxic or physically harmful.” His move has triggered a political and legal battle, with many Republican governors vowing to fight the mandates in court. The mandates raise several new questions regarding this vague statute: Is a virus a “…toxic or physically harmful substance?” Does COVID-19 present a “grave danger?” Has the executive branch exceeded its authority in offering a solution to a problem previously reserved to the states? Do these mandates violate the 14th Amendment by depriving workers of their personal liberties? It is important to note that Biden’s mandates do not actually make vaccines compulsory: The government may levy a fine or forbid a child from attending school, but no American will be forced to get an unwanted jab. This has not always been the case.

There are historical precedents for vaccine mandates and even for forced vaccination.

In February 1991, five Philadelphia children died from measles, a disease that was mostly eradicated in the US, due to vaccination. Measles once sickened millions of kids, each year hospitalizing ~50,000 and killing close to 500 before a successful vaccine was developed in 1963. After that, cases dropped dramatically as all states mandated measles shots for school children. Vaccine hesitancy and resistance were rare because people saw the tangible success of the measles vaccine.

But, in Philadelphia that winter of 1991, the serious cases of measles came from a single source, a church cult that rejected “…all means of healing apart from God’s way.” Church members took no medicines, owned no thermometers, and saw no doctors. Rejecting all birth control, they raised large families in close quarters, a recipe for the measles epidemic, which they cooked. Trying to contain the threat to the rest of the city, officials worked through the courts to gain access to the homes of the congregants and received the authority to vaccinate the children against the wishes of their parents. In this public health emergency, defending the parents’ anti-vax actions was close to impossible. Even the ACLU took a pass.

Vaccine mandates even appeared during the Revolutionary War. George Washington mandated that all his troops be immunized against smallpox, even against their will. He described smallpox to Virginia’s Governor Patrick Henry as “more destructive to an Army in a Natural Way, than the Enemy’s Sword.” As I wrote earlier in these pages, smallpox had doomed the Colonial Army’s assault on Quebec in 1775, and it threatened Washington’s main force. Washington’s mandate proved a brilliant gambit and smallpox largely disappeared from the ranks. Some historians point to the mandate as a major factor in winning the war against the Brits.

During that war, smallpox vaccination entailed a primitive vaccination procedure known as variolation. That involved opening a lesion from an infected person and scraping its contents into the arm of a recipient. It was effective, but the vaccinated person became quite ill for a couple of weeks, and about 3% of them died from the pox. Later, in 1796, the English scientist Edward Jenner discovered a much safer method of immunization using cowpox, a virus similar to smallpox that did not cause significant disease in people. But the new smallpox vaccine got a mixed reception in the US as some resisted it for reasons of personal safety based on the variolation experience. They rationalized, “what good could possibly come from polluting the body with dangerous foreign matter?” Or, “Why challenge the plans of the Creator?” Still, Jenner’s vaccine was a clear improvement over variolation and drove a steady decline in smallpox outbreaks throughout the 19th century. States began passing laws mandating smallpox vaccinations for school children, and some forcibly vaccinated prisoners, paupers, and orphans.

In 1905, the issue of vaccine mandates reached the Supreme Court in the seminal case of Jacobson v. Massachusetts. Henning Jacobson, a Lutheran pastor in Cambridge had defied a city ordinance requiring smallpox vaccinations during an outbreak. He refused to pay a $5 fine so he was arrested. Jacobson posited that “healthy and law-abiding” people like himself (even though he was disobeying the law at the time) posed a minimal danger to the community. He argued that even if his refusal to be vaccinated led to him spreading the smallpox virus, the only victims would be others “who failed or refused to be vaccinated.” In other words, he reasoned that it would be ok to not get the vax because the vaxed would be safe, but wholly ignored the rights to safety of those who were not vaxed. 

It is an argument that is repeated today about the CoV-2 vax. Using modern science that was not available in the early 20^th century, experts have repeatedly refuted this argument, explaining that many people who want the vax cannot be fully vaccinated because they are immunocompromised, or allergic to the vaccine’s contents, or do not have access to the vaccine. Also, we now know that the more RNA viruses, like the coronavirus, are allowed to spread, the greater the chance more deadly variants can appear. Jacobson’s contention that the decision to vaccinate solely belongs to the individual, not to the state, employers, or to medical authorities remains a central tenant of today's anti-vaxers.

The Supreme Court disagreed with Jacobson. The majority opinion, written by Justice John Marshall Harlan, asserted that “the liberty secured by the Constitution does not import an absolute right in each person to be at all times, and in all circumstances, wholly freed from restraint.” Rather, he argued, the Constitution rests upon “the fundamental principle of the social compact…that all shall be governed by certain laws for the protection, safety, prosperity and happiness of the people, and not for the profit, honor or private interests of any one man, family or class of men.” Jacobson had not only broken the law, the court suggested he also had violated the principle upon which a well-ordered society depends. We are not wholly independent the court ruled. The greater good of the community can trump individual rights.

Using Jacobson as precedent, the Supreme Court in 1922, upheld a local ordinance in San Antonio requiring proof of smallpox vaccination for people entering “public schools or other places of education.”  

Later, during World War II, the US military made vaccines mandatory for a host of diseases, such as typhoid, yellow fever and tetanus, and it still mandates certain vaccines for troops in certain deployments. Soon after the war very successful vaccines were developed against several childhood diseases like polio, measles, mumps and chickenpox. Guided by the Supreme Court’s ruling in Jacobson, all 50 states put laws on the books mandating many of these vaccinations for school children. Even today, many school districts and colleges mandate certain vaccines for students and staff. Hospitals, too, often mandate certain vaccines for their staff. Until lately, vaccine mandates have not generated much angst and anger.

Why is this? Perhaps vaccines have done their job too well: Many of them have erased the tragic evidence of why they were needed in the first place. The world no longer deals with small pox, thanks to the vaccine. Almost no one in this country has seen someone ravaged by polio, or a child hospitalized with measles, or who lost his hearing due to chicken pox, all thanks to vaccines. Yet, now with COVID-19, anti-vaccine anxieties have found their way into the political mainstream, especially among conservatives. An estimated 80 million American adults remain unvaccinated against COVID and represent potential factories for producing the next deadly coronavirus variant, which is very preventable.

As I have addressed before in these pages, many factors fuel resistance to the life-saving shots, including doubts about their quick development and their possible long-term effects. But a growing distrust of professional expertise, including medical science, has also played a role, which is unwarranted. Who are you going to believe, a medical scientist like me with nothing to gain in the debate (except the safety of my friends, family, and self), or someone who read a web post from folks who are selling nostrums they claim will protect you, like Dr. Steve Hotze, or from one of America’s Frontline Doctors whose web site claimed that gynecological problems were caused by having sex with demons? Do you jump on the side of those who tout that their individual freedoms have been abridged, but who do not consider the freedoms from disease of the greater community, and whom the courts already have decided against?

Almost 300 years ago, Benjamin Franklin struggled over whether to have his sons variolated against smallpox. In his “Autobiography,” he worried that well-meaning people were tragically misjudging the calculus between the risks and benefits of the procedure, as he had once done, with a tragic result. He wrote, “In 1736, I lost one of my sons, a fine boy of four years old, by the smallpox….I long regretted bitterly and still regret that I had not given it to him by inoculation. This I mention for the sake of the parents who omit that operation, on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that, therefore, the safer should be chosen.”

HIV And Coronaviruses: A Bad Combo

Africa is the continent least vaccinated for COVID-19 and it also has been where several CoV-2 variants have arisen: Beta in South Africa, most recently C.1.2 (not yet given a Greek letter designation) also from South Africa, and Eta in Nigeria. A possible reason for the appearance of these variants is because Africa is also home to the most immunocompromised people. HIV is common in Africa and tuberculosis is rampant on the continent.

One HIV-positive woman in South Africa was reported to carry active CoV-2 infection for 216 days, during which time it mutated 30 times according to Tulio de Oliveira, who runs gene-sequencing centers at two South African universities. This is concerning since South Africa has the world’s largest HIV epidemic. It is estimated to have 8.2 million people infected with HIV. While most of these take antiretroviral drugs, which keep the virus at bay, many do not. And neighboring countries, Botswana, Zimbabwe, and Eswatini also have very high HIV infection rates. The burden of HIV, TB and other chronic diseases is higher in these countries than in other countries around the world due to extreme poverty and poor health care for millions of Africans. When these people also become infected with CoV-2, they grow and shed the virus longer than someone with a good immune system and good health care. That means that the virus has longer to mutate in an infected, immunocompromised person.

In wealthier countries in the West, a rich debate is ongoing about whether to add another shot (booster) to already vaccinated people. One of the biggest arguments against this is that those booster vaccines are needed much more in poorer, and woefully under-vaccinated countries, such as those in Africa. The concern is that our boosters come at the expense of basic immunization of these impoverished countries, which facilitates the generation of troublesome viral variants. On the other hand, if CoV-2 is running rampant because the health care infrastructure in these countries is not up to delivering those vaccines, maybe it would be better making sure that richer countries are as protected as possible.

These are the proverbial two horns of a dilemma. Which horn would you choose?