The virus that causes coronavirus disease 2019 (COVID‑19) attaches to specific molecules on the host cell surface, opening accesses into the cell interior.22 Viral entry into host cells can cause an overwhelming immune response in some patients. Much of this immune response is focused within the lungs, which explains why many patients hospitalized with COVID‑19 have severe respiratory symptoms. In addition to respiratory symptoms, there is also blood vessel inflammation, neurological symptoms, including dizziness, headache, nausea, and loss of concentration.22 These symptoms indicate that SARS‑CoV‑2 affects cells of the central nervous system. A recent study reveals that the spike proteins that are on the surface of SARS‑CoV‑2 promote inflammatory responses on the endothelial cells that form the blood-brain barrier.22 It is also known that SARS‑CoV‑2 infects host cells by using its spike proteins to bind to the ACE2 receptors on the host cell surface.22

In efforts to create a transparent interpretation of SARS‑CoV‑2 protective immunity, antibody analysis has been paralleled by T‑cell studies among patients with asymptomatic, mild, and severe COVID‑19.23 Defining CD4 and CD8 effector functions in protection is important, considering that antibody responses to natural infection appear short-lived and T‑cell memory is potentially more durable. To fully understand population-level immunity, screening for both antibody and T‑cell immunity using standardized testing methods may would be beneficial.23

To appreciate the ongoing propagation of the virus, to identify those who are and were infected, and to follow the immune response longitudinally, reliable and rigorous analyses for SARS‐CoV‐2 detection and immunological monitoring are needed. SARS‑CoV‑2 antibodies are detectable up to seven months post symptomatic COVID‑19 onset, and a recent study shows that 90% of subjects have detectable antibodies 40 days up to 7 months post contracting COVID‑19.24 The study then evaluated the function of these antibodies, namely, their neutralizing activity against the virus SARS‑CoV‑2. The study emphasizes a continued level of circulating neutralizing antibodies in most people with confirmed SARS‑CoV‑2.24

The clinical symptoms of individuals affected by the virus are diverse, ranging from mild upper respiratory symptoms to severe pneumonitis, and in some acute respiratory distress syndrome (ARDS) or death.25 Early symptoms may include cough, shortness of breath, or at least one of the following: fever of 100.4 degrees Fahrenheit or higher; chills, shaking, muscle pain, headache, sore throat, or loss of taste/smell.91 To best understand these symptoms, it is important to evaluate how the SARS‑CoV‑2 virus interacts with the innate and adaptive host immune response. The body's first line of defense, the innate immune response, including complement and the cellular immune response, is initiated after an infection is detected, with the intent to destroy viral particles and any cells damaged by virus. Further, the second line of defense, the adaptive immune response, is initiated days later if any virus remains. The adaptive immune response leverages exposure to viral materials to develop antibodies and other mechanisms through T‑cell and B‑cell mechanisms. It has been shown that an interaction between the body's two main lines of defense may be causing the immune system to go into overdrive in some patients.

Cytokines have been found that play a crucial role in the development of these clinical features and are also at the core of the development of inflammation. Systemic immune hyperactivation due to SARS‑CoV‑2 infection causes a cytokine storm, which is especially noteworthy in severely ill patients with COVID‑19.25 When SARS‑CoV‑2 infects the body, the inflammatory response performs an antiviral role, but a strong cytokine storm caused by an overactive host immune response can be very damaging to the patients. A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines.26 Suppressing the cytokine storm is one way to treat critically ill COVID‑19 patients. The cytokine storm is a potentially fatal inflammatory syndrome that is caused by elevated levels of circulating cytokines and immune cell hyperactivation that can be triggered by various therapies, pathogens, cancers, and autoimmune conditions.27

Illustrated diagram of COVID-19 cytokine storm response
Illustrated diagram of increased cytokine levels of COVID-19 patients
COVID‑19 Cytokine Storm Response.28

Many people believe that microbes, such as bacteria, viruses, and fungi, that enter the body to initiate disease should be feared most during an outbreak of an illness such as influenza, but the contribution of the host immune system is potentially more lethal.

This is analogous to the pathophysiology of periodontitis, wherein bacteria initiate disease, but the disease progression is mitigated by the host immune-inflammatory response.29 When the body identifies foreign microorganisms signaling an infection, it might respond by over-protecting the site of infection. It may quickly react, and numerous antibodies quickly migrate to the infection site and upregulate host pro-inflammatory reaction and cytokine formation. Typically, cytokines are a component of the immune response to infection, to protect our bodies, but their sudden release in large quantities can cause multisystem organ failure and death.27 Cytokine storms can be caused by several infectious and non-infectious etiologies, but are especially prevalent in viral respiratory infections such as H5N1 influenza, SARS-CoV-1, and SARS‑CoV‑2.

The prevalence and tenacity of antibodies following a peak SARS‑CoV‑2 infection provides understanding of its dissemination in the community, the likelihood of reinfection, and potential for some level of population immunity. One of the questions about COVID‑19 is whether people who are infected with the virus are immune from reinfection, and if so, for how long. Researchers studied the production of antibodies from a sample of nearly 6,000 people and found immunity persists for at least several months after being infected with SARS‑CoV‑2.30 The study found that high-quality antibodies were being produced five to seven months after SARS‑CoV‑2 infection. The research provided the ability to accurately test for antibodies against COVID‑19, as well as presented the knowledge that lasting immunity is a reality.30

Alternatively, the conclusions of other studies show that antibodies created against SARS‑CoV‑2 after natural infection are not long-lasting. One investigation found that up to 40% of individuals with previous COVID-19 infection lacked convalescent antibodies25 and another study measured antibody levels in a group of 37 COVID‑19 patients three to four weeks after initial infection, then two months thereafter. Nearly 20% tested negative for antibodies completely, indicating either total disappearance or undetectable antibody levels.31 Further, it is not known what level of protection to the virus, if any, is provided by post-infection antibodies. Therefore, it is challenging to state with confidence whether this potential rapid dissipation of the antibody response after initial COVID‑19 infection leaves the body vulnerable to reinfection.

Some reports have postulated that the T‑cell response against coronavirus infections, including those caused by SARS‑CoV‑2, endures longer than the antibody response.32 T‑cells are a form of white blood cells that, like antibodies, are vital to our ability to prevent future confrontations with a harmful virus.33 In the case of seasonal coronaviruses associated with the common cold, T‑cell memory to a pathogen has little to no effect in preventing re-infection, which can occur once or more times per year.

Understanding the roles of different subsets of T‑cells in protection or pathogenesis is crucial for preventing and treating COVID‑19. Like B‑cells, which produce antibodies, T‑cells are key players in the immune response to viral infections. CD4+ T‑cells help B‑cells to produce antibodies and help CD8+ T‑cells to kill virus-infected cells. Evolving studies imply that all or most people with COVID‑19 develop a strong and broad T‑cell response, both CD4 and CD8, and some have a memory phenotype, which signifies the potential for longer-term immunity.32,33

It has been indicated that the influenza vaccination might reduce the risk of COVID‑19.34 Patients who have received an influenza vaccine were found to have 24% lower odds of testing positive for coronavirus disease 2019 (COVID‑19).34 Those who were vaccinated against influenza and tested positive for COVID‑19 were more likely to have better clinical outcomes than those who were not vaccinated.34 While the cause of this association is unknown and could reflect the healthcare and infectious-disease attitudes of those individuals who received the influenza vaccination, influenza vaccination was associated with decreased positive COVID‑19 testing and improved clinical outcomes and should be promoted to potentially reduce the burden of COVID‑19.34

It might seem implausible that a vaccine designed to protect against one infection could protect against others as well. But a growing body of research suggests that this can occur through a process called “trained innate immunity.”35 Vaccines are known to work by stimulating the adaptive immune system, causing the body to make antibodies that can recognize and attack a specific pathogen if it is encountered again.36 However, recent studies suggest that some vaccines also train the body’s faster-acting and less specific innate immune system, improving its ability to fight off many kinds of infections. Vaccines appear to achieve this act by reprogramming stem cells that give rise to cells involved in this early innate immune response.37