The Immune System.
Free will may be defined as the power to act in the absence of the constraints of fate. We can choose whether to socially distance ourselves, wear masks, and wash our hands frequently—simple solutions that are more than 90 percent effective at preventing the spread of COVID-19 (SARS-CoV-2). For myriad reasons beyond the scope of this review, many Americans exercised their free will in a different direction, and the virus spread from zero cases to more than 28.3 million in just over 12 months.
Fortunately, the body’s immune system operates beneath the level of conscious thought to protect us even when our volitional choices don’t. This system is incredibly efficient, so-much-so, that more than 97 percent of those infected with COVID-19 ultimately recover. The network starts with our innate immune system, an inherent, at-the-ready defensive cooperative that includes barrier protections, cellular activation, and a host of physiologic and inflammatory responses. Examples of barrier defenses include skin, mucus membranes, and the millions of tiny hair-like projections known as cilia that line our airways, sweeping upward at a rate of 16-times per second—all working to keep things in good order. Mucus is sticky and gooey for a reason.
In addition to barrier defenses, there are physiologic protections that include the acid in our stomach and the lysozyme in our tears. Fever is another example of a defensive physiologic response. Fever inhibits viral and bacterial replication, promotes white blood cell phagocytosis (internal ingestion) of pathogens, and activates T-lymphocytes that help the body combat infection. Protein interferons, produced by cells infected with viruses, circulate to protect uninfected cells. Meanwhile, different proteins found in the blood, lung, and mucus, known as collectins are capable of directly killing bacteria by disrupting their cell membranes, while also promoting clumping that enhances phagocytosis. Then, there is the complement system, a group of inducible plasma proteins that bind directly to the surfaces of microbes, targeting them for destruction by white blood cells.
Next in the lineup are mediators of inflammation; chemicals released in response to injury or infection that trigger vascular and cellular changes to mitigate further damage. These chemicals include cytokines, vasoactive peptides, and acute-phase reactants like CRP (C-reactive protein) that culminate in the well-known features of inflammation (redness, warmth, pain, and swelling).
Batting clean-up are the granulocytes, white blood cells that include neutrophils, eosinophils, and basophils/mast cells. Neutrophils are highly active phagocytic cells that play an essential role in combating bacterial infections. Eosinophils are involved with fighting blood-borne cancers and parasitic infections, while also playing a role in asthma, allergies, and certain connective tissue disorders. Basophils (in the blood) and mast cells (in the tissues) are responsible for the release of histamine and other substances involved in allergies. The innate immune system is a vast network of interrelated cells, tissues, and reactions that function both dependently and independently from one another to keep us healthy.
Finally, the innate system includes circulating monocytes and tissue macrophages. These cells play critical roles in antigen presentation, phagocytosis, and cytokine production. And here is where the innate system overlaps with the adaptive immune system. While the former is constitutive and non-specific, the latter represents an inducible, pathogen-specific response to infection. The adaptive immune system comprises both humoral (B-cell) and cell-mediated (T-cell) immunity, the former directed against pathogens circulating in the bloodstream while the latter is primarily involved with the destruction of intracellular pathogens. Both are needed to combat COVID-19 that invades cellular tissues and circulates through the bloodstream.
Antigens are foreign proteins and polysaccharides capable of eliciting an immune response, whereas antibodies are internally derived proteins synthesized by B-cells in response to an antigen challenge. Antibodies chemically combine with surface antigens of bacteria, viruses, and foreign substances, targeting them for recognition and destruction. In the bloodstream, the presence of high circulating levels of IgG antibodies against the COVID-19 spike protein is indicative of recent infection or active immunity.
B-cells are produced in the bone marrow and circulate in the bloodstream before traveling to lymph nodes where they mature and differentiate. B-cells (bone marrow-derived) are capable of independently recognizing antigens to promote an immune response, but function much more efficiently and with a stronger memory response when activated by T-helper cells residing in lymphatic tissue. Once presented with an appropriately packaged antigen, B-cell clones unique to that antigen differentiate either into IgM antibody-producing plasma cells or memory cells that continue to reside in lymph nodes. This process of cloning and differentiation takes several days to ramp-up, during which time infected patients often become symptomatically ill. As the process continues, activated plasma cells begin producing IgG antibodies specific to the particular antigen (in the case of COVID-19, the spike protein and several other surface proteins). Although IgM is the first antibody produced, smaller IgG antibodies are more efficient at binding to antigens and neutralizing pathogens. In patients with a history of past antigen exposure, memory cells are capable of generating a rapid and robust IgG response that prevents subsequent illness. This is the basis of immunity.
T-cells (thymus-derived) play a critical role in the process. Both T-cells and B-cells are types of lymphocytes. T-cells are further subdivided into CD4 cells (T-helper) and CD8 cells (T-killer). Each type is capable of recognizing a different histocompatibility complex specifying the T-cell response; one for intracellular activation against viruses and cancer cells, the other for extracellular activation against bacteria and parasites. Like B-cells, activated T-cells then undergo clonal expansion that results in both effector T-cells to combat active infections and memory T-cells to safeguard against future ones.
T-helper cells stimulate B-cells to secrete antibodies, induce macrophages to destroy microbes, and assist in the activation of T-killer cells that ultimately recognize and destroy cells infected with viruses. To combat a wily foe like COVID-19 requires the help of the innate immune system, both arms of the adaptive immune system, and our own volitional choices, in addition to the innovative efforts of researchers and scientists in developing a number of effective therapeutics put into play by thousands of dedicated healthcare workers. Nonetheless, despite the gargantuan effort of the collective and the incredible healing powers of the individual, more than a half-million American have lost their battle with COVID-19, while countless others continue to suffer long-term effects of the illness. COVID-19 is now the leading cause of death in the US, and in one year has killed more Americans than the WW I, WW II, and Vietnam combined. This is why vaccination remains our best—and likely only—way out of this mess.
COVID-19 is one of seven known coronaviruses capable of infecting humans, four of which cause mild upper respiratory tract infections. Two others—SARS (Severe Acute Respiratory Syndrome) and MERS (Middle-East Respiratory Syndrome)—caused outbreaks of deadly diseases that quickly faded. COVID-19, more virulent than its URI-causing cousins but less so than either SARS or MERS, has shown no signs of spontaneously resolving. Now, well into its second winter, the virus has demonstrated remarkable staying power irrespective of seasonal conditions. The emergence of new strains in the UK, South Africa, and Brazil has only served to complicate an already complex situation. But we are not passive observers. What we choose to do, and choose not to do, matters.
The virus itself is a model of simplicity—a bit of genetic material (RNA) encased within a glycoprotein membrane adorned with an array of spike proteins. The spikes contain binding sites that allow the virus to invade host cells, releasing its genetic material into the host cell cytoplasm where it then high-jacks host machinery to transcribe and translate copies of the proteins that make up mature viruses. After assembly, these viruses are released into the bloodstream to repeat the process many times over. The result is exponential growth.
Fortunately, these same proteins that adorn the coat of the virus and portions of the membrane are immunogenic, capable of provoking both humoral and cell-mediated immune responses. Given adequate time, the body’s response is sufficient for most patients to recover. In some, however, the infection overwhelms the body’s defenses, resulting in severe disease and death. Although advanced age and chronic medical conditions increase the odds of a bad outcome, the disease also strikes young healthy people, managing to kill a few of them seemingly at random. Some children will later become critically ill with a diffuse inflammatory condition following an otherwise mild infection with COVID-19. This, too, appears to arise arbitrarily. It is not yet possible to predict who will get incredibly sick from this virus and who will not. COVID-19 demonstrates a broader spectrum of pathogenicity than any previously encountered infectious disease, ranging from a complete lack of symptoms to multisystem organ failure, ICU admission, and death. The virus is capable of causing damage to virtually every organ in the body including the lungs, heart, liver, kidneys, brain, and blood. Clots are common with this virus, as are abnormalities of liver and kidney function. I have seen acute strokes in young adults and pulmonary emboli in older ones as a result of infection. The unpredictability of this virus is another reason why vaccination represents the best option for just about everybody.
There are several paths to immunity. Passive immunity occurs when pre-formed antibodies are administered to previously unexposed individuals. This is a way of jump starting the immune system. Examples of passive immunity include antibody transmission from mother to child through breast milk, and use of the HRIG (Human Rabies Immune Globulin) after exposure to rabies (administered simultaneously with a separate series of vaccinations to induce active immunity). In COVID-19, the use of convalescent plasma and monoclonal antibodies represent types of passive immunity. The drawback is that passive immunity is incomplete and transient. Nor does it prevent future infection.
Alternatively, active immunity confers long-term—often life-long—protection against subsequent infection. It occurs in one of two ways; either following an active infection or via the administration of a vaccine. Note that not all infections confer immunity. While infection or vaccination is sufficient to provide life-long immunity against small pox and measles, the same doesn’t hold true for other simple infections like strep throat or the common cold. When it comes to COVID-19, nobody knows the duration of immunity conferred after an active infection with the virus. There have been rare instances of re-infection. Nor is the duration of protection after vaccination known with certainty. Ultimately, controlling COVID-19 may require a series of boosters similar to the TDAP (Tetanus, Diphtheria, and Pertussis) vaccine or even annual vaccination as with influenza. Nonetheless, current COVID-19 vaccines are extremely effective at preventing symptomatic disease in the short-term. This is a key concept to ending the pandemic. When enough people have immunity, either through active infection or vaccination, the pool of available hosts shrinks to a point where the virus is no longer a viable contagion. This is the fulcrum for herd immunity. For COVID-19, current best estimates are that between 70 to 85 percent of the population requires immunity to protect the rest. We still have a long way to go.
There has never been a disease in human history to spur as much research in so short a time as the COVID-19 pandemic. Within months of the release of the genetic sequence of the virus by Chinese researchers in January 2020, there were more than 100 vaccine candidates in development, employing multiple vaccine platforms funded through a variety of innovative private, public, and public/private funding collaboratives. While traditional vaccine platforms have employed either live attenuated strains or killed strains of the microbe in question (e.g. the MMR and Salk polio vaccines, respectively), vaccines in development against COVID-19 include whole virus, viral sub-unit, DNA-based, RNA-based, and viral-vector vaccines. Two mRNA vaccines (Moderna and Pfizer) have been approved for use in the US through the issuance of EUAs (Emergency Use Authorizations), with a third viral-vector vaccine (Johnson & Johnson) approved for use just this weekend. Approval under an EUA does not mean that short-cuts in safety and efficacy were taken. Rather, it means an expedited approval based on the results of current available trials in the setting of a medical emergency for which alternative treatments are limited or non-existent.
All three vaccines work remarkably well.
(Part 2 discusses the specifics of the vaccines, their administration, side-effects, and ACIP scheduling recommendations.)
- Nan-Chang Chiu et al., “Impact of Wearing Masks, Hand Hygiene, and Social Distancing on Influenza, Enterovirus, and All-Cause Pneumonia During the Coronavirus Pandemic: Retrospective National Epidemiological Surveillance Study,” J Med Internet Res 2020; 22 (8): e21257.
- J. Paces et al., “COVID-19 and the Immune System,” Physiol Res 2020; 69 (3): 379-88.
- Angela Clem, “Fundamentals of Vaccine Immunology,” J Glob Infect Dis 2011; 3 (1): 73–78.
- Akiko Iwasaki1 and Saad Omer, “Why and How Vaccines Work,” Cell 2020; 183: 290-95.
- Lianpan Dai and George Gao, “Viral Targets for Vaccines Against COVID-19,” Nat Rev Immunol 2021; 21 (2): 73-82.
- Yen-der Li et al., “Coronavirus Vaccine Development: From SARS and MERS to COVID-19,” J Biomed Sci 2020; 27: 104.
- Simran Preet Kaur and Vandana Gupta, “COVID-19 Vaccine: A Comprehensive Status Report,” Virus Res 2020: 288: 198114.
- Vladislav Izda et al., “COVID-19: A Review of Therapeutic Strategies and Vaccine Candidates,” Clin Immunol 2021; 222: 108634
- Joost Wiersinga et al., “Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review,” JAMA 2020; 324 (8): 782–93.
- Tahmineh Mokhtari et al., “COVID-19 and Multiorgan Failure: A Narrative Review on Potential Mechanisms,” J Molecular Hist 2020; 51 (6): 613-28.