immunity

Paxlovid: Just Follow The Settled Science

“We will see…”

-Yours Truly

Precis: “Just follow the science.” “The science is settled,” etc. We have all heard these bromides only to be later instructed that we need to follow a different science truth, or that the science firmament has shifted. Frustrating isn’t it? You must think that scientists must be a wad of weasely, waffling, wags in white coats certain of only uncertainty. One day we sagely advise you that something is certain truth, the next day we say that new research says that something else is true because, well, we know and you just need to trust us. We know because we did those ephemeral, sacred rituals called studies that give us all-knowing wisdom that we then impart to you who should worship us. 

That, I hope you know, is the cynical view of science, which sometimes is deserved. But, there is another side of things, which should be heeded. That side is that everything technology-based; from medicine, sanitation, lights, electricity, cell phones, transportation, etc.; that we enjoy using and take for granted, was created by that same science. These two sides of science often collide and greatly confuse non-scientists, which is most people. That is a shame and that is why I blog—to try to reduce some of the confusion.

Paxlovid, a drug highly touted as the only oral medicine to treat COVID is a great example.

Backstory: Paxlovid was initially given emergency use authorization (EUA) for treating COVID by the FDA in 2021 because of promising preliminary observations. Clinical trials performed by its manufacturer, Pfizer, then quickly showed solid, eye-popping results that made the drug an overnight sensation. It demonstrated an 89% reduction in the risk of hospitalizations and deaths in infected individuals. It also shortened the disease and reduced the symptoms of those with mild to moderate COVID. All this lead to the NIH to prioritize it over other COVID treatments under investigation at the time. In other words, NIH put R&D on other potential anti-COVID drugs on the back burner because they had found an effective one.

Paxlovid was the first effective oral anti-viral treatment for COVID. It basically works by blocking a key enzyme the virus uses to make new virus particles. A second medicine in the drug is an old treatment for HIV/AIDS which affects liver metabolism of that key enzyme blocker allowing it to linger longer, thereby boosting its antiviral effect.

The only drawback to Paxlovid is that it needs to be started shortly after infection to be effective. It also interferes with several common medicines so some patients either have to forgo taking some of their regular medications for a while or avoid Paxlovid. Nevertheless, it has been quite beneficial for reducing COVID symptoms in infected people and preventing severe COVID disease.

What is new? Ok, now you can forget everything about Paxlovid you read above. A new clinical trial, also done by Pfizer, and just published in the New England Journal of Medicine, showed that Paxlovid does not help patients get symptom relief or reduce the incidence of severe COVID and hospitalization. In other words, Paxlovid had zero effect on COVID in the study just published.

Thus, the makers of the drug now have two studies with diametrically opposite results on the effects of Paxlovid on COVID patients. The first showed “eye popping” effects sufficient to get NIH to move all other drug investigations to a lower priority. The second showed that Paxlovid was no better than a placebo.

At this point, I suspect many readers are rolling their eyes and thinking this is just another example of “settled science” unsettling the “suckers” who listen to the weasely, waffling, wags in white coats. Well, unroll your eyes. Both results are right.

Say what? Yes, it is likely that both results are accurate because the two Paxlovid studies were done on quite different populations.

The first study, which showed a dramatic positivie effect of the drug was done pre-vaccination. The study population did not have the advantage of vaccine protection against COVID. The second study was conducted post-vaccines and the participants had the advantage of already being partially protected against severe COVID symptoms. That protection rendered the Paxlovid effect meaningless. It showed that the the drug doesn’t do much if you have been keeping up with your vaccines, and it shows the value of the vaccines.

Kudos to Pfizer for conducting and publishing the results of both studies, especially the second one. The results of the second study certainly will ding Pfizer’s bottom line, but it was an exercise in honest science. Still the results of the study do not leave Paxlovid totally off the COVID treatment radar. First, the study did not indicate that the drug is ineffective for high risk vaccinated patients, such as immunocompromised patients. And in the US, we still, unfortunately, have many un- and under-vaccinated people who would benefit from Paxlovid when they catch COVID. Finally, while this Pfizer trial involved about 650 test subjects, a much larger trial involving a few thousand subjects soon will be forthcoming from the UK.

So, if you are vaccinated and catch COVID, it is not crucial to get to your doctor in time to get on Paxlovid. And the UK trial might address additional questions that will tell us more about the value of Paxlovid in treating COVID. We won’t know until its study results are released. In other words:

We will see.

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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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Why Don’t The COVID Vaccines Last Longer?

The FDA just authorized a second booster shot of the Pfizer-BioNTech and Moderna coronavirus vaccines for people over 50 and the CDC has approved it. A second booster has already been approved in the U.K., Sweden, Israel and Denmark.

Why do we need a second booster only months after the first booster, which came only months after most of us received two jabs of either the Pfizer-BioNTech or Moderna mRNA vaccines? Are the vaccines not very good? After all, we get small pox or measles shots that last a lifetime. Others, like the vax for tetanus, last for ~10 years. Why can’t we get a more durable coronavirus vaccine?

The answer is complicated and largely rooted in both viral biology and vaccine immunology.

Viral biology. The simplest answer is that viral mutation can change the molecules the vaccine immune response is trained to recognize, causing vax immunity to decay as viruses mutate. The coronavirus vaccines are directed against the spike protein expressed on the original CoV-2 that first appeared in Wuhan, but that ancestral bug has spawned mutated progeny that look a bit different to the immune system. In other words, viral variants created by “antigenic drift” become less recognizable to the immune system. That is why the vaccines are somewhat less effective against the Omicron variant that carries numerous point mutations in its spike protein. The current vaccines are still pretty effective against current viral variants, but continued antigenic drift along with the selection of variants that can better avoid vaccine immunity will likely require new vaccines in the future.

So, why do we need new flu vaccines every year, and need frequent CoV-2 vaccines, but we don’t similarly need new measles vaccines? Measles, mumps, flu, COVID, and other diseases are caused by viruses, but the different viruses behave quite differently. Viruses carry relatively little genetic material that tends to mutate as they replicate and spread. Some viruses, like flu, also have a “segmented genome” meaning that their genetic material is carried on several separate genetic molecules, making it easy to shuffle their genomes like a deck of cards when different flu strains infect the same animal. Other pathogens carry all their genetic material on a single DNA or RNA molecule making such gene shuffling between strains less likely, but it still happens. Also, the mutation rate of a pathogen’s genome is a function of its replication rate; hence, each time a bug copies its genome, small random errors are inserted into its genetic code. The more the bug replicates, the more mutations will accumulate in its genome and the faster replicating bugs will more rapidly create new variants. Thus, the measles virus is pretty stable since it does not replicate as much as a coronavirus or a flu virus, so it is not surprising that vaccine immunity to measles is much more durable. Smallpox and polioviruses also have relatively low replication rates and vaccine immunity to them also is long-lasting. In contrast, flu and coronaviruses replicate rapidly and pass back and forth between humans and animals. This means that they mutate rapidly and need frequent vaccine updates.

Other vaccines, such as the TB vax, target bacteria not viruses. Bacteria carry larger genomes that are not so changeable, so anti-bacteria vaccines also are pretty long-lasting compared to many anti-viral vaccines.

Yet other vaccines, such as those against tetanus, diphtheria, and pertussis do not even target the pathogen at all, but target toxins produced by the bugs. Vaccinated people produce antibodies that neutralize the toxins and this prevents disease. These vaccines do not forestall infection, they simply prevent the ill effects of the pathogen. Therefore, for these toxoid vaccines, there is no immunological selective pressure to select pathogen variants that can avoid vax immunity. Vaccines against these toxins also tend to be among the longest-lived vaccines.

Vaccine immunology. Vaccines aim to mimic natural immunity we develop to infection with pathogens. By exposing the body to harmless imitations of a pathogen, vaccines create an immune response and immune memory against pathogens, while avoiding the disease caused by the bugs. When an infection does occur in a vaccinated person, a rapid and robust immune response is mounted, first with B-cell generated antibodies that latch onto the invaders and prevent them from spreading and causing illness. Then T-cells secret cytokines that further ramp up the inflammatory response, and other T cells attack pathogen-infected cells. As explained earlier in these pages, antibody responses tend to linger only a few weeks to a few months and then gradually decay. This is good; otherwise your blood serum would be like syrup from all the antibodies against all foreign things you encountered over your lifetime. While antibodies circulating in your blood are good for quickly attacking infections shortly after infection, they do not confer long-term immunity. What confers long-term protection is what are called memory cells. These are a relatively few T and B cells that go dormant after fighting an initial infection or responding to a vaccine, but hang around awaiting a new infection to signal them to quickly roar back to life and mount a vigorous response against their cognate pathogen. This secondary response to a previously seen pathogen is much faster and usually nips the bug in the bud so you don’t even know you were infected.

When we hear that CoV-2 immunity decays only a few months after vaccination, the reports usually refer to declining levels of anti-CoV-2 antibodies, which happens naturally. Such announcements do not take into account your immune memory, which is harder to measure, but which is a better metric of your long term immunity. The problem also is that we simply have not had enough time with the vaccines to know how long their immune memory persists. It seems relevant that a study published in July 2020 reported that people who were infected with SARS in 2003 maintained robust T cell immunity 17 years later. So far, indications are that even though antibody levels fall over time, immunological memory after vaccination also remains robust. This is seen by the continued protection from serious disease and death in vaccinated people with low antibody levels. The vaccines and the immune memory they stimulate are working. How long that memory persists is unknown. Time will tell.

So why are we getting the booster shots? In the face of a raging pandemic caused by a novel pathogen, the cautious approach is to keep antibody levels at a protective level in vaccinated people until we better understand the extent of long-term protection brought on by our immune memory. The boosters, therefore, represent a cautious approach to maintain an effective antibody defense during these still early months of a novel pandemic. We likely will reach a time where world-wide immunity from vaccination and natural infection will give us baseline protection that will render COVID-19 mostly a bothersome disease rather than a life threatening infection. Until then, the boosters are a good idea to help us maintain an effective antibody defense against serious disease.

The natural pathology of measles is instructive here. Even though antibody levels typically decline after most immunizations, antibodies produced after a measles vaccine persist for many years. This happens with some other, but not all, vaccines too, but why? In countries where the measles virus is endemic, repeated infection of vaccinated people keeps the antibody immune response in continual high gear. That is not the case with the flu virus which changes rapidly and bypasses last years shot. Interestingly, measles has been eradicated from the US and Western Europe, so vaccinated people are not continually exposed and re-exposed to the virus and, unlike for those who live in endemic areas, our anti-measles antibody levels decline. Therefore, our long-term protection against the virus is due to our immune memory and not due to antibody levels.

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Updated: Over 65? Roll Up Your Sleeve Again

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The Washington Post just reported that Pfizer and its partner-in-vax, BioNTech, plan to seek emergency authorization for a second CoV-2 booster for those of us 65 and older (you know who you are). It is intended to beef up immunity that wanes a bit a few months following the previous booster.

US data show protection against severe COVID illness is robust after the first booster, but falls somewhat from 91 percent effective in preventing severe illness to 78 percent effective over several months. Still, 78% protection is very good, but given how transmissible Omicron is, and the possible emergence of the Son-of-Omicron, which might be even more infectious and virulent, the idea behind a second booster is to offer people the chance to acquire the greatest level of protection possible. Not a bad idea.

The data that will be submitted to the FDA in support of the 2nd booster probably will include real-world data collected in Israel, which has already rolled out the second shot, and has reduced infections and serious illness in people older than 60. This will likely not be the last CoV-2 vax we will see. Pfizer and BioNTech are also working on a vaccine more effective against all variants and provide more lasting protection. That remains on the horizon, so stay tuned.

For those of us 65 and older, we (at least the males in that demographic) remember draft cards. As we entered our later years, the draft card, if unburned, was replaced in our wallets with our AARP cards, and then accompanied with our Medicare cards. Now we need a new wallet pocket to accommodate our vax card.

On a personal note about cards, your maturing and slowing bloggeur admits favoring a certain grocery store in town because they still card him when he buys his bottles of 80 proof anti-vax remedies.

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Update: Three days after this was first posted, Moderna announced that it also has asked for FDA approval for a second booster. However, they ask that the booster be approved for all adults over 18, and not just for those over 65 as Pfizer/BioNTech have done. This request, like the one submitted by Pfizer/BioNTech is largely based on recent data from Israel

Moderna made a strategic decision to request approval for all adults in order to give the FDA flexibility in deciding which patients would be good candidates for the booster. In other words, they could decide that it also would benefit under 65 and so recommend.

 

 


Has Omicron Rendered Vaccines Ineffective?

Early in the pandemic, when we realized that the CoV-2 virus was quickly producing mutated progeny, some of which were becoming more deadly and transmissible, some (including your humble blogger) warned that viral mutation could feasibly give rise to a variant that ignored immunity to previous iterations of the germ—in other words able to ignore the current vaccines. We have arrived—almost.

The so-called omicron variant partly avoids immunity conferred by the current vaccines (and by prior infection), meaning that we are seeing “break-through” infections in fully and partially  immune people. Popular news sources are running headlines declaring that vaccinated patients with COVID are filling hospital beds, leading many to leap to the conclusion that the vaccines have failed.

But, that is not fully accurate. Many vaccinated people are indeed getting infected with omicron, yet the vaccines are still quite effective, and much better than no vaccine. Let me explain.

First, about two-thirds of Americans are vaccinated—a definite majority of the population. This means that for a hypothetical virus that can fully evade immunity, there are more vaccinated than unvaxed viral “targets” available; meaning more vaccinated than unvaccinated people will be infected. The reality, however, is that the vaccines are still partly protective so that many vaccinated people still catch omicron COVID. Yet, compared to vaxed people, unvaccinated people remain at significantly greater risk of infection, hospitalization, and death. Numbers in my State of Wisconsin, bear this out.

Currently, 69% of the State adult population is vaccinated. According to the latest data* (as of January 15, 2022), out of 100,000 vaccinated people, 1573 caught COVID, 18.5 were hospitalized, and just under 4 died. In contrast, out of 100,000 unvaccinated people, 4,746 got infected, 176 were hospitalized, and 51 died. In other words, many more unvaccinated adults are feeling the effects of COVID, despite representing only 30% of the State population. Clearly, there were breakthrough infections in vaccinated people, but just as clearly, unvaccinated people fared way worse than they would have if they had the shot.

Yet, the headlines persist, proclaiming things like, “Similar numbers of vaccinated and vaccinated people hospitalized for COVID.”   Does this not show that the vaccines are no longer effective? Not at all. Because many more people are vaccinated and partly susceptible to the virus, more and more vaccinated people are showing up with infection, but at a much lower rate than unvaccinated people do. The graphic below illustrates how this works.

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The benefits of the vaccines also are reflected in national and world-wide numbers. The US has one of the lowest vaccination rates among developed countries such as the UK, Canada, Norway, Denmark, etc. And despite omicron’s “milder” nature, which means it kills fewer people but still kills, the COVID death rate in the less vaccinated US is greater than seen in more vaccinated countries, attesting to the efficacy of the shots. Also, new hospital admissions in the US have now reached an all-time high and far exceeding hospitalization rates in better vaccinated countries. Current data from New York State shows that hospitalization among the unvaccinated is 14x higher than among fully vaccinated people.

All of this demonstrates how effective the vaccines remain at preventing infection, hospitalization, and death from omicron-driven COVID. Places with higher vaccination rates, such as the UK and Canada, are not experiencing an increase in base case rates of patients admitted to the ICU or deaths, even with omicron cases skyrocketing. The US is.

Get your Fauci boo boo.

*Note on Wisconsin State data sources: State data mentioned here are from the Wisconsin Department of Health Services, Public Health Madison and Dane County, and the Wisconsin Hospital Association as reported Jan 15, 2022 in the Wisconsin State Journal.


Naturally Immune? You Still Better Get A Vaccine

Over 43 million Americans have reported cases of COVID-19. Many of them likely have some level of immunity that can be quite protective, even without vaccination. Even before vaccines were available, individuals who recovered from COVID-19 had detectable T-cell responses, and reinfections were rare, at least prior to the emergence of the more contagious Delta variant. This is what people refer to colloquially as “natural immunity,” to distinguish it from immunity conferred by vaccination. Some people claim that natural immunity is better and preferable to vaccine immunity and that a history of infection should count as much as being vaccinated when considering vaccine mandates. Is all this true? Well, like what we have seen and heard during the pandemic, a lot of truths have been spread, same with lies and disinformation. The story around natural immunity follows this pattern. Let me try to sort all this out here with a focus on whether previously infected people should consider getting vaccinated.

Natural infection can confer immunity to COVID. Like most viruses, previous infection with SARS-CoV-2 does confer immune protection against future re-exposure to the virus. Several peer-reviewed studies conducted in the early months of the pandemic, before vaccines were available, found that people previously infected were around 80% less likely to test positive for the virus during the next viral surge. These included studies of healthcare workers in the UK, the Danish population, and patients at the Cleveland Clinic, a large health system in Ohio and Florida.

Other data from the UK Office for National Statistics showed that between May and August 2021, a prior infection offered around the same level of protection against the Delta variant as vaccination. (Note that very recent and preliminary observations in South Africa suggest that infection with the new Omicron variant is high in people previously infected with other CoV-2 variants. However, since Omicron is so new and data on it are very sketchy at this time, this review will not further comment on this variant.)

A recent large Israeli study found that people who had been fully vaccinated with two Pfizer shots were 13 times more likely to later get infected with CoV-2 than those who had a prior infection. It also suggested that immunity from infection was longer lasting than that from vaccination. The study also showed that natural immunity plus the vaccine offered protection that was even stronger than either natural or vaccine immunity alone. This is one of the very few studies suggesting that natural immunity is better than vaccine immunity and has not been peer-reviewed. Furthermore, the subsequent rise of Delta since the end of this study confounds the issue a bit since Delta has been shown to be more infectious than the viruses the study subjects were exposed to. 

In the most recent review of the current scientific evidence by the CDC, they concluded that both fully vaccinated and those previously infected with the virus have a low risk of re-infection for at least six months, but that the two forms of immunity appear to have different strengths. Vaccination with mRNA vaccines produced higher concentrations of neutralizing antibodies—the type that prevent the virus from entering cells—than natural infection, although, over time, the antibody levels waned in both groups. However, long lasting immune memory conferred by natural infection appeared to be stronger than that conferred by vaccination.

Over time, immune B cells typically evolve to produce antibodies that better recognize an antigen, and an earlier study published in Nature found that antibodies produced by naturally immune memory B cells continued to evolve at least a year after infection. In contrast, antibodies produced by memory B cells in vaccinated people did not change much over time. This would suggest that over time, antibodies produced by natural immunity gain greater ability to respond to re-infection with the virus than antibodies produced by vaccination. One possible reason for this difference in the evolution of the anti-viral antibodies was that pieces of virus remain in the body for weeks after infection and continue to engage the immune cells, whereas vaccine lipid nanoparticles quickly fade away providing less immune stimulation. 

On the other hand, vaccine immunity might be better. So, as we have seen, a few reports suggest that natural immunity is superior to vaccine immunity. However, more studies suggest the opposite and even show that not everyone who catches COVID-19 will have effective immunity to re-infection. A CDC study reported that 36% of previously infected people did not form any antibodies against the virus. This is in stark contrast to antibody formation reported in 100% of people who received just one dose of an mRNA vaccine. Furthermore, the CDC reported in August that COVID survivors who went unvaxed were more than twice as likely as vaccinated people to get infected again contrasting with the Israeli study I mentioned earlier. Yet another CDC study looking at data from ~190 hospitals in nine states confirmed that unvaccinated people who survived an infection several months earlier were more than five times more likely to get COVID again than vaccinated people.

The reason that natural immunity might not always be effective is because the natural exposure to the virus is highly variable. People naturally infected are exposed to widely different doses of virus via different routes and possibly to different viral strains, all of which conspire to confer different degrees of protection. In contrast, vaccinated people receive standardized doses of the same viral antigen via the same route of exposure, making them more likely to develop a uniform degree of immunity. Researchers found that some people who had been infected had high antibody levels to the virus, while others had low levels, reflecting this variability in natural infection. This was substantiated by a new study from the University of Pittsburgh that also found that in many cases antibody levels from a prior infection are not high enough to protect people from getting sick again. Then, an Oxford study found that both long term T and B cell immune responses were highly variable in naturally immune people. The investigators took monthly samples of blood from infected subjects and measured their T and B cell responses over time. Interestingly, the variability in their responses was clearly identified as early as one-month post infection. Those with the weakest immunity at one month (25% of the subjects) had no detectable antibodies after six months. This contrasts to vaccine immunity, which does fade a bit over six months, but still remains consistently strong months after full vaccination. 

Finally, new evidence from an NIH-supported study from the Fred Hutchinson Cancer Research Center, Seattle showed that antibodies from vaccinated people better recognized the mutated spike proteins from viral variants than antibodies from naturally immune people who had not been vaccinated. In other words, vaccinated people seem better able to respond to mutated spike proteins present in new viral variants.

The bottom line. In sum, while natural immunity can be effective, most evidence shows that vaccines typically give rise to consistently better antibody and long term T and B cell responses.

Having made this point, it is important to further note that a combination of both types of immunity, or so-called hybrid immunity, appears to be stronger than either alone. Researchers found that vaccination of naturally infected people boosted antibody and memory B cells to levels higher than seen in those with just either type of immunity. People with prior COVID-19 who received even one vaccine dose had half the risk of a breakthrough infection than unvaccinated people with prior COVID-19. Another study from researchers at the Icahn School of Medicine in New York found that a single dose of either the Pfizer or Moderna vaccines produced more antibodies in people who had previously had COVID-19 than two vax doses did in those who had never encountered the virus. It also found that people with prior infection report more unpleasant, but not serious side effects from vaccination. Vaccinating previously infected people also elicits important cross-variant neutralizing antibodies that better protect them against the known viral variants. Hybrid immunity also appears to work in the other direction: A study of vaccinated people who were then infected during a July 4 holiday weekend outbreak on Cape Cod found that they produced higher levels of antibodies and T-cells directed against the virus. In sum, vaccination helps those with natural immunity (and everyone they interact with) and vice versa

For these reasons, the CDC now recommends that people who have had COVID-19 be vaccinated because the shots plus natural immunity have been shown to offer better protection than natural immunity alone.