Infection vs. Vaccination Acquired Immunity

Four reasons for differences in durability and protection.

Much like masks and risks to children, comparisons of immunity acquired by vaccination or by recovery from SARS-CoV-2 infection have become highly politicized. As an immunologist, I find this incredibly frustrating. A refusal to acknowledge what is known about protective immunity and the continuous employment of manipulative messaging will do very little to influence public behavior. I suspect it is having the opposite effect.

Up to half of the population of the United States has recovered from SARS-CoV-2 infection. The vast majority acquired the virus through no fault of their own; simply engaging in normal human behavior increased the risk of infection. Much like any natural disaster, the damage from a global pandemic could only be minimally contained. Non-pharmaceutical interventions have not stopped viral transmission, and were considered temporary measures prior to 2020, although improved pharmaceutical treatments have likely improved patient outcomes, especially with the increased use of anti-SARS-CoV-2 monoclonal antibody therapies.

Yet the key to ending the pandemic has always been the immune system. The fact that so many have recovered from infection and that robust, durable, and protective immunity in those individuals has been unequivocally proven should be considered a good thing. Yet somehow, it isn’t. Many still seem to believe that acknowledgement of protection of infection-recovered individuals will result in masses of people having COVID parties and hospitals being overwhelmed, since one can’t eliminate the risk of severe disease by getting infected. As a result, there appears to be a drive to cancel the term “natural immunity”, a pretense that the vaccinated need fear the unvaccinated, and an unwillingness to treat the public as adults that can handle nuanced information and make decisions regarding their health. However, I believe the biggest problem for political and public health leaders is that they cannot take credit for immunity acquired by infection.

Vaccination is different. With vaccination, immunity is acquired without the risk posed by infection. Vaccine technology has been advancing for decades, making the development of SARS-CoV-2 vaccines much faster and easily scaled for mass production. The development and distribution of vaccines is something that public health officials and politicians can and most certainly will take credit for, as well as reduced hospitalizations and deaths in the vaccinated population. For them, it’s a win-win proposition.

However, there are also differences in immunity acquired by infection compared to immunity acquired by vaccination. This is true for any infectious disease, including respiratory infections with SARS-CoV-2 and influenza, and thus I will use examples for both. And since the majority of people in the United States have been vaccinated with either Pfizer or Moderna vaccines, I will stick with these when making comparisons. Thus far, Pfizer and Moderna vaccines have been shown to induce high levels of protective antibodies against the spike protein of SARS-CoV-2 along with T cells that can kill infected cells or help other cells perform their antiviral functions. Yet it appears that the potency of immune protection in vaccinated individuals may wane over time, most importantly, in individuals who are already vulnerable to severe disease. This is why boosters are now becoming available for the most vulnerable people.

Here are four reasons why immunity acquired by infection is different than immunity acquired by vaccination:

1) The route of exposure influences the resulting immune response.

In response to a respiratory viral infection, an immune response begins after viruses infect and spread among cells in the airways. This results in the activation of many airway and mucosal-specific immune responses. In the lungs, the lymphatic system drains to lung-associated lymph nodes, where T cells and B cells become activated after recognizing their specific antigen, which consists of pieces of viral proteins that can bind to the T or B cell surface receptors. In lung-associated lymph nodes, these cells are “imprinted” by activation of specific molecules that help them migrate to lung tissues. B cells get specific signals to make antibodies, including a specific type called IgA that is secreted into airways. When an individual recovers from infection, some of these immune cells become long lasting lung-resident and memory cells that can be activated and targeted much more quickly during a reinfection and thus limit spread in the lungs and disease severity.

In response to a vaccine, the immune response starts in the deltoid muscle of the arm. The spike protein of the virus is produced in muscle cells, and spike-recognizing T and B cells in the arm-draining lymph nodes (in the armpit) are activated. The T cells that are activated do not express lung-homing molecules, and neither do the memory T cells that develop later. Activated B cells secrete virus-neutralizing antibodies, but little mucosal IgA is produced. If an infection occurs, memory cells from vaccination will respond quickly, but there won’t be many located in or immediately targeted to the lung, and viral-binding IgA won’t immediately block airway cell-invading viruses.

2) Viral antigen may persist after infection, but is less likely to persist after vaccination.

This is an important difference between influenza vaccine-induced and infection-induced immunity. Even after symptoms have resolved and live virus has been cleared, the lungs still harbor a reservoir of influenza proteins and nucleic acids that continuously stimulate the development of immunity for extended periods of time. That doesn’t happen in response to vaccine injection, where inactivated virus stimulates an immune response that is cleared quickly and efficiently. Scientists are working on ways to develop vaccines that mimic this antigen persistence to stimulate longer-lasting immunity to influenza vaccination, with some proposing viral antigen packaged in slow-degrading nanoparticles.

It is very likely that antigen persistence also occurs during SARS-CoV-2 infection, as viral mRNA and antigens have been detected for months in the small intestines of previously infected individuals. It is unknown how viral nucleic acids and proteins persist after clearance of infection, but it appears to be an important factor in the development of durable antiviral immune memory. In contrast, spike proteins produced by mRNA vaccination may only persist for a few days, thus limiting the time for stimulation and subsequent memory development.

3) Most SARS-CoV-2 vaccines only stimulate immunity against the spike protein.

The spike protein of coronaviruses allows for virus attachment to and invasion of host cells. A strong immune response to the spike protein will result in the production of antibodies that prevent the virus from binding the viral receptor (ACE2) on human cells, thus preventing or slowing viral spread. The vaccine consists of mRNA that only codes for the SARS-CoV-2 spike protein, and is packaged to allow cells to uptake spike mRNA and translate the message into protein. That makes those muscle cells look like they’ve been infected to the immune system, which responds with activation and multiplication of spike-recognizing T and B cells.

In contrast to this limited scope of immunity in response to vaccination, T and B cells are activated in response to infection that recognize all parts of the virus, including the nucleocapsid and other viral proteins. Although antibodies to these proteins are less likely to block viral entry of host cells, more T cells will recognize these antigens and will be able to kill infected cells due to a broader activation of the immune repertoire. However, this also increases the opportunity for autoimmune pathology (as does any strong immune response), which is an important contributor to severe SARS-CoV-2 infection. In other words, stronger protective immunity comes with a tradeoff of a higher potential for immune destruction and long-term effects.

4) More viral replication produces more particles that stimulate stronger immune responses inside and outside of cells.

The immune system is able to recognize and differentiate active viral replication inside cells compared to replication of self-DNA and transcription into mRNA. As viruses infect neighboring cells and spread, this results in a strong signal to local immune cells that help activate T and B cells. Although an mRNA vaccine mimics this signal, spike proteins can’t replicate beyond the spike-encoding mRNA contained in the vaccine, and as a result the signal isn’t as strong and doesn’t affect as many cells, limiting the strength and durability of downstream immunity. This is overcome to some extent with a second dose and with a booster vaccination, which will improve the quality of antibody binding in some indviduals, but not others.

Conclusion

Both immunity to vaccination and infection protect against severe disease, but the scope of immunity that develops after infection is broader, generally more durable, and more specific to lung reinfection. Stronger immunity derived from infection comes with increased risk of severe disease and a higher incidence of long-term effects, especially in older people and those with comorbidities. Despite the obvious downsides, misinformation about the inferiority of “natural” immunity to vaccination persists, likely out of fear that data showing long-lasting protective immunity from infection will promote vaccine hesitancy. However, the pandemic will not end due to vaccination alone, but due to a combination of vaccine-acquired and infection-acquired immunity, despite the unwillingness of politicians, scientists, and public health officials to admit it.