Let’s Talk About Immunity

The historical vaccination for smallpox, caused by variola, was inoculation with cowpox, vaccinia – two microbes that were similar but not the same. [1] 

Advances in science brought us Salk’s polio vaccine, where the poliovirus infectivity was inactivated, but its immunologic signature maintained – similar, but not the same. Through multiple passages through cells and animals, Sabin’s polio vaccine lost its ability to cause disease. It kept its immunologic signature, but its virulence was attenuated – similar but not the same. [2] 

Similar is an ambiguous term. How close does one need to be similar? 4.1 is similar to 4, 4.2 a little less so, 5 maybe not at all. The newest vaccines, the mRNA vaccines, are closer to the 4.1 than the 5. They provide only the immunologic signature to COVID-19’s spike-receptor binding domain (RBD) – once again, similar, very targeted, but not the same. This strategic target was chosen because the binding to our cells and the subsequent replication of the virus begins there.

The immunologic signature of COVID-19 among those who acquire their immunity the old-fashioned way, by becoming ill with COVID-19 and hopefully surviving, is different. In this instance, the immunologic signature is to the RBD and two other spike areas, its N terminal domain (NTD) and S2 subunit. NTD and RDB mutations are present in COVID-19’s Delta variant. The S2 subunit seems to be less mutable; it is conserved in the variants. It may be a more advantageous strategic immunologic signature to target moving forward. 

Primer Reminder

Our immune system’s Paul Revere are dendritic cells found on our borders, where we meet the world, our skin, and blood. When they identify a foreign antigen, they signal danger and “present” that antigen to our immune system, initiating a response by our B and T cells. The B cells produce antibodies. In the case of the mRNA vaccines, to the RBD, in the case of immunity acquired through infection, to the RBD, NTD, and S2 subunits. B cells make antibodies for some time—when we speak of the waning strength of the vaccine’s immunologic response, we are talking about the B cells making fewer antibodies, T “helper” cells assist in the production of the antibodies by the B cells. T “killer” cells identify infected cells and “take them out.”

Our immunologic memory resides in both the B and T cells. B memory cells are already primed to create antibodies when exposed a second time to a foreign antigen. T central memory cells stimulate the dendritic cells to begin their “midnight ride,” while T effector cells rush to the site of infection to help in the B cell response. 

Immune Memory

"The body doesn't really forget. Usually, when we get reinfected with a disease, it's not because our body has lost immunity. We get reinfected either because the pathogen mutated and our immune system no longer recognizes it, or because our bodies tend to mount a much lower immune response.”  

Dr. Marc Jenkins, immunologist, University of Minnesota Medical School 

When we wonder about how long the COVID-19 vaccines will last, we are really pondering our immune memory. In some instances, like measles, our immunity is one and done. Measles, our most contagious airborne virus, is genetically remarkably stable. It doesn’t change over time. Moreover, it provokes a very robust immune response; so robust that it was estimated to produce antibodies to measles for more than 200 years, so robust that it can “reset” your immune system, replacing its old memory cells with those directed solely at measles—creating what is termed "immune amnesia."

Chickenpox, caused by the varicella-zoster virus, loses its antibodies after around 50 years, so it is rare to see a second case of chickenpox. On the other hand, our immune response is not as robust as it is to measles. The varicella-zoster virus may lie dormant in our cells until we are older and it is reactivated with a new name, shingles, or herpes zoster. You might consider the shingles vaccine a booster for your prior chickenpox immunity. 

Some have argued that our immune response is bolstered by frequent subclinical, asymptomatic infections that keep our immune response heightened. The tetanus vaccine creates antibodies that persist for about 11 years, and we are rarely re-exposed to tetanus. That is why every time you have an injury where tetanus may be of concern, the doctor gives you a booster.

COVID-19, unlike measles, does mutate, hence the variants of concern (VOC). For a first-order approximation it mutates in a way similar to seasonal flu, which changes sufficiently that the immunologic signatures targeted by our seasonal flu vaccines change annually and differ between the Northern and Southern hemispheres. And we have no certain data on how persistent immunity to COVID-19 and its variants lasts. 

Just as measles may make our immune system forget other pathogens it has experienced, other microbes that are similar but not the same may enhance our immunity. A series of experiments in ferrets, which share our susceptibility to respiratory viruses, have demonstrated that the history of our exposures to antigens can alter our immune response. Similar microbes may be sufficiently reminiscent to provoke an immune response. In a study now being reported in Science, researchers found T cells taken from individuals who have had the “common cold,” about 90% of the population, had in some instances a cross-reactive response to COVID-19. The response was weaker and faded more quickly, especially among the elderly. But for some of us, a history of a recent “cold” contributes to a subsequent immune response to COVID-19.  

When it comes to immune memory, you might consider that vaccines try to be faithful mimics of immunity acquired from the disease itself. So, if the disease is one and done, like measles or polio, the vaccine will likely behave similarly. COVID-19 is more like seasonal flu, so we are more likely to require updated vaccines over time. 

What makes a foreign antigen similar but not the same

The surface configurations of a microbe, its overall shape are the result of the microbe’s genetics and the proteins, fats, and sugar created by its genes that form its outer layer. Those components create spatial and energetic forces that can interact with our cells. For COVID-19, the site of action is the spike where the configuration allows it to alter the surface of ACE receptors and fuse with the cell. From there, COVID-19 injects its genetic material into the cell, hijacks the cellular machinery, reproduces, and is released to find new ACE receptors and continue replicating. 

Our understanding of these spatial and energetic forces comes from physical and organic chemistry, from how a catalyst alters the configuration of a chemical and allows it to interact with chemicals surrounding it more easily. But biological chemistry is not as precise as organic chemistry. The molecules and cells result from the transcription of genes into proteins and other cellular building blocks, and the system can make errors. As Dr. Bloom has noted, the Delta variant differs by only one amino acid from its less virulent cousins. 

To visualize the difference between naturally acquired and vaccine-induced immunity, consider a plane with those funny wings that turn up at the ends – those parts are call winglets. [3] And consider two weapons designed to stop the aircraft. The first specifically targets the winglet. If you remove the winglet or make it smaller, it will alter the plane's performance, but it will still fly. But our weapon will find targeting more difficult; the winglet is not as expected. All the COVID-19 vaccines target the RBD portion of the spike. That makes good sense because it prevents infection by inhibiting the binding of the virion to our cells inhibiting infection. It also was a quick, “warp speed” solution.

Natural immunity acquired the hard way, by surviving a COVID-19 infection, is a different weapon. Like the mRNA vaccines, it targets the RBD portion but also two other areas on the spike. To extend my metaphor, it targets the front edge or perhaps the flaps of the wing. It is capable of recognizing its target even if the winglet is changed or removed. Now theoretically, that suggests that natural immunity because it responds more broadly to the virion provokes a more robust immune response – hence the discussion of why get vaccinated if you already “had COVID-19.”

Our best, current, real-world data shows that this is not the case, that reinfections among those with naturally acquired immunity are roughly 2.5 greater than those with vaccine acquired immunity.  

Factors impacting mutation

Each organism has its own internal rate of change, roughly based upon the precision of its transcription of genes into building blocks. COVID-19 lies closer to seasonal flu, which frequently changes, than to measles and polio that change “not at all.”

The dance between the virus, its mutations, and susceptible hosts is what Darwin meant in describing survival of the fittest. Viral mutations increase as the number of infected hosts increase. Some of these mutations confer an advantage to the host; our immune system rapidly eliminates the virus with these mutations. Other mutations confer an advantage to the virus - allowing it to bind more easily, reproduce to higher levels before we recognize we are ill, or even survive longer outside a host. Those viral mutants, we call them variants of concern, are fitter and multiply more quickly, becoming predominant. COVID-19 alpha fades away, and the new and improved Delta, Lamba, or maybe Mu, variant predominates. 

The current COVID-19 vaccines are not fully protective, but they significantly reduce the number of susceptible hosts, the first step in the rise of viral variants of concern. Masks and social distancing add to the reduction in susceptible hosts. They make the environment less fit for the virus. 

In their re-arranging of our internal parts, surgeons try to alter the “playing field” to your and their advantage—we want to more than level the field; we want it tilted in our direction. Vaccination, and to a lesser but still important degree, the non-pharmaceutical interventions of masks and social distancing, tilt the field in our favor, making it more difficult for the virus to find another host. The unvaccinated “collaborate” with the virus, creating a playground of hosts where it can mutate and come back to bite us all. 

[1] Cowpox resulted in a milder, less harmful disease.

[2] As an interesting contrast, all of the discussion about the gain in function research is just the flip side of Sabin’s and his predecessor, Max Theiler’s work, on loss in function.

[3] Their purpose is to reduce the drag on the wings, thereby increasing efficiency and reducing fuel requirements.