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Blog #38: Immunology’s role in pandemics, infectious disease, and COVID-19 (Part 4: Therapy)
Care for coronavirus patients is supportive in nature and may include rest, supplemental oxygen, fluid administration, and, for critically ill patients, being managed in intensive care units and receiving rescue therapies such as extracorporeal membrane oxygenation (pulmonary ventilation). Stringent infection control is critical to prevent transmission to caretakers, healthcare workers, and other patients. Personal protective equipment (PPE) including surgical or procedure masks, gown, gloves, and face shields) are indicated during the treatment of all coronavirus patients, and such protocols for droplet-spread respiratory viruses that are part of hospital infection control practices. Masks as preventive care for all persons are indicated, but public (and even political) resistance has proven to be an obstacle in this simple, but most valuable protective measure.
General measures
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Test all populations, especially those suspected of infection (tests listed below);
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All positives should be isolated and “contact traced” (“if possible”) to identify “patient 0” and/or persons who may have come into contact with the infected person. They too should then be tested;
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Shelter-in-place or “self-isolation” (remain in your home with only absolutely necessary outdoor activities);
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Social distancing (separation of > 6 to 10 feet between people);
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Avoid gatherings of more than 5 to 10 people;
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Wash your hands copiously and frequently;
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Face masks (at first CDC and surgeon general suggest for use only if infected, now it’s strongly recommended for full-time use - N90 masks preferable);
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If symptoms occur (fever, cough, chills, aches, and pains), get tested and if positive, self-quarantine for a minimum of 14 days and retest 2X before resuming normal activities;
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If symptoms advance over 2 to 3 days, seek medical attention;
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Mitigation: process includes procedures and policies to reduce risks of infectious spread;
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Modeling
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Study the mechanisms by which disease is spreading (i.e., investigative epidemiologic and public health analysis);
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Monitor (graphically) through testing positive case volumes, death rates, and other vital statistics;
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Hospital admissions;
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Intensive care admittance;
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Extracorporeal membrane oxygenation (pulmonary ventilation)
Treatments
It appears that SARS-CoV-2 infection has two phases. The early phase includes the infectious stage (approximately 3 to 9 days) where the virus is replicating followed by the later stage (7 to 21 days) where the disease is driven by an exaggerated immune/inflammatory response to the virus. This is the phase that leads to tissue damage, organ failures, and oftentimes, post-COVID syndrome or long haulers syndrome. Based on this understanding, and as has been shown in clinical outcomes, antiviral therapies would have the greatest effect early in the course of time and are unlikely to be more beneficial in the later stages (beyond 5 to 7 days) of the disease.
If I may, I would like to ask you over the coming week to do a quick review of Blogs #20 through 23, 25, 26, 31, 32, and 34, all of which provide the basic science and applications of the immunotherapeutic drugs and procedures. Almost all of them are being used in the treatment of COVID-19 (and many other infectious diseases).
Blog #39: Immunology’s role in pandemics, infectious disease and COVID-19 (Part 5: Immunotherapies: Using our bodies to fight back)
This is a continuation of our discussion on the treatment and management of COVID-19 and infectious diseases in general. We’ll start with specific information on immunotherapies regarding their use in infectious diseases (I hope you reviewed some of the previous blogs mentioned last week addressing immunotherapeutic drugs and procedures. If not, it’s not too late.)
Immunotherapy
Antiviral drugs and some immunotherapeutics show beneficial effects in the early phases of the disease and monoclonal antibodies, biologics, and corticosteroids in the later phases during the potentially more aggressive immune/inflammatory stages. Monoclonal antibodies are also used asap upon infection. When administered early in the infectious period they serve as an effective antiviral agent to reduce the viral load in the nasopharynx. The effects of monoclonal antibodies and other drugs on viral load may prove to be an important criterion for the development of agents to treat early Covid-19.
Monoclonal antibodies and biologics:
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Bamlanivimab (effective in early stages);
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Combination of casirivimab plus imdevimab (most effective in early stages and high risk for progressing to severe disease and/or hospitalization);
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Interleukin-6 receptor antagonists (suppressing ILK-6);
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Tocilizumab and sarilumab have also been shown to improve outcomes and survival rates, especially when used in combinations;
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Regeneron (combination of casirivimab and imdevimab called REGN-COV2, effective in early stages);
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Bamlanivimab (LY-CoV555) is a single monoclonal antibody (delivered in 3 doses of 700 mg, 2800 mg, and 7000 mg);
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Cytokine inhibitor drugs (e.g., checkpoint inhibitors, IgG, Interleukin 6 blockers) are being studied and beginning to show some benefits in advanced cases and late-stage infectious diseases and COVID-19.
Convalescent plasma (serum)
Plasma is collected from the blood of patients who have recovered from COVID-19. The red and white blood cells are separated and put back into the donor’s bloodstream while the blood plasma, rich with virus-fighting antibodies are kept aside. Monoclonal antibodies are isolated from patients and showed that the patients had strong immune responses against the infecting viral protein, a complex that binds to receptors on the host cell. From this information, a subset of antibodies from the serum can be used to neutralize the virus. Nonetheless, the results of convalescent plasma treatment continue to be equivocal.
Dexamethasone (and glucocorticosteroids)
A readily available, inexpensive corticosteroid, dexamethasone, has been found to improve survival in hospitalized patients who require supplemental oxygen and demonstrate elevated levels of inflammatory biomarkers. For patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. Several therapeutic interventions have been used to mitigate inflammatory organ injury (see chronic inflammation discussion in Blog #16) in viral pneumonia including glucocorticoids (i.e., dexamethasone). They have been widely used in syndromes closely related to Covid-19, including SARS, MERS, severe influenza, and community-acquired pneumonia. The evidence to support or discourage the use of glucocorticoids under these conditions is inconclusive. Other steroids are also beginning to show some promising results during the early stages of the disease.
CRISPR-Cas13 and RNA screening
A new Cas13 RNA screen (vs. Cas 9 from Blog #26) has been developed to establish guide RNAs for the COVID-19 coronavirus and human RNA segments that could be used in vaccines, therapeutics, and diagnostics. Similar to CRISPR-Cas9, a novel Cas13-based editing tool targets mRNA (vs. DNA for the Cas9 enzyme) and knockout genes without altering the genome. Using the CRISPR-Cas13 enzyme, researchers have created a genetic screen for RNA, currently designed for use in humans that they say could also be used on RNA containing viruses and bacteria. Developers have used the parallel-screening technique to create optimal guide RNAs for the SARS-CoV-2 coronavirus that could be used for future detection and therapeutic applications.
Next up are infectious diseases and COVID-19, Antiviral drugs (Blog #40), and vaccines (Blog #41).
Different from vaccines that manipulate the body’s immune response to a virus and its genetics, antiviral drugs attempt to boost the immune defense to inhibit viral development. They block receptors so viruses cannot bind to and enter healthy cells and they lower the amount of active virus in the body. Antivirals may be broad-spectrum and treat a variety of viruses while others target a specific viral protein to disable the virus and remain nontoxic to the host cells. Thus, most antivirals are considered relatively harmless to the host, and thus can be used aggressively (large dosages) to treat infections (e.g., acyclovir). Among the antiviral drugs being used since the COVID-19 pandemic, some have proven to be effective in certain forms and variants and have been given FDA emergency or full-use authorization. Other drugs, FDA-approved for uses other than antiviral therapy have been promoted as having antiviral qualities based on anecdotal evidence. Hydroxychloroquine (Plaquenil), a biologic used for malaria and lupus, combined with azithromycin (Zithromax), and Ivermectin, an FDA-approved drug to treat certain forms of
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parasitic worms, are 2 of the drugs questionable or wholly ineffective in the treatment of coronaviruses and having even shown adverse effects.
Paxlovid (nirmatrelvir/ritonavir) is a protease inhibitor, similar to those used against HIV. SARS-CoV-2 uses its cellular enzymes (protease) to replicate its RNA-containing “polyproteins” (see Life Cycle, Blog #35). By blocking the enzyme’s activity, the drug prevents the production of new, functional viral particles. Paxlovid is quickly broken down in the body, so it needs a booster in the form of a second drug called ritonavir (also a protease inhibitor) to keep it active for a longer period in the host. Notwithstanding potential drug-drug interactions, these drugs have shown significant promise with a 90% reduction in hospitalization rates.
Molnupiravir (Merck/Ridgeback Biotherapeutics) is known as a nucleoside analog that mimics one of the RNA proteins that make up SARS-CoV-2. Once inside cells, the virus uses a polymerase enzyme to attach to its RNA and assemble them into new copies of viral RNA. The virus needs a template for the construction of new viral RNA and molnupiravir interrupts this template and causes the virus to continuously mutate until it virtually destroys itself with defective genetic material. Due to some side effects from the drug, it is used only in high-risk patients with advanced disease.
Remdesivir is antiviral drug thought to interfere with the mechanism that coronavirus uses to make copies of itself (see Fig. 7.1 and Life Cycle). A preliminary report published in The New England Journal of Medicine showed that the drug shortened recovery time for people with COVID-19 from an average of 15 days to about 11 days. The drug also seems to show increased benefits when used in combination therapies (e.g., with Baricitinib and monoclonal antibodies). It is recommended for use in hospitalized patients who require supplemental oxygen.
Other developing antiviral drugs for COVID-19 will continue to be developed as adjunctive therapies to vaccines and any other evolving immunotherapeutic measures to COVID-19. No doubt by the time you are reading this, beyond all of the drugs and treatment modalities listed below and mentioned in this section, there will be an array of new therapeutic measures being implemented for patient treatments and hopefully, for prevention:
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Interferons: antiviral cytokines under investigation;
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Lopinavir/Ritonavir and other HIV protease inhibitors;
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Nitazoxanide: antiparasitic drug under investigation;
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Lopinavir/Ritonavir and other HIV protease inhibitors;
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Fluvoxamine: an antidepressant pill as an anti-inflammatory;
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Budesonide: an inhaled steroid used to prevent asthma symptoms.
By definition, a vaccine is a biological preparation that provides active, innate, and adaptive immunity to a particular infectious disease (e.g., measles, flu, SARS-CoV-2) by stimulating antibodies or manipulating messenger RNA (mRNA) to attack the source of the infection. The traditional approach has been to develop an agent that resembles the disease-causing microorganism made from fragments of the offending microbe (attenuated, a weakened or inactivated form or a viral vector, genetic copy of a virus), its toxins, or one of its surface proteins. This process induces a subclinical antigen stimulus that is recognized by the immune system that produces corresponding immune cells and antibodies but without inducing clinical disease. In the novel coronavirus, the spike protein was targeted for most of the vaccine human clinical trials. The greatest success (as of early 2022) against the RNA novel coronavirus used genetic instructions in the form of messenger RNA (mRNA) to prompt a subclinical immune response from the virus.
The science of the mRNA vaccine is an elegant model of immunology and genetics technology (Fig. 7.2). An RNA virus (e.g., novel coronavirus) means its genetic material is encoded in RNA rather than DNA. Once the virus is inside our cells, it releases its RNA and makes long viral proteins to compromise the immune system (see Fig. 7.1). genomic proteomics (transcription and translation – see Blog #10) produce copies of the virus’ surface receptors (spike proteins, in the case of novel coronavirus). Then, as the patient’s immune system recognizes a “foreign invader,” it initiates an APC/Th and TC response (remember those from Blog #5?) that release Th cells that generate cytotoxic TC and B cells. The TC cells go to work doing their job of phagocytizing (engulfing and destroying) the virus while the B cells generate antibodies that bind and block the virus from infecting healthy cells. Goodbye virus, at least for 6 to 12 months they are projecting at which time booster shots are indicated.
One of the weapons in our cells is an RNA surveillance mechanism called nonsense-mediated mRNA decay (NMD) that protects us from many genetic mutations that could cause disease. The genome of COVID-19 is a positive-strand single-stranded RNA that can evade NMD and prevent it from degrading RNA by producing proteins that interact with certain proteins that modify the chemical structure of RNA. With the progression of new viral strains, the mRNA vaccines can be easily genetically reprogrammed to recognize mutant viral
strains (called variants) and allow for the rapid development (within weeks) of second-generation vaccines that directly target processes critical to a virus’s life cycle.
CRISPR-Cas13 (see Blog #26 for CRISPR description) offers the potential for a broad-spectrum antiviral (BSA) RNA screening to inhibit many SARS-CoV-2 variants. Cas13d-mediated coronavirus inhibition is dependent on the crRNA combining with Cas13d and targeting viral RNA. It can significantly enhance the therapeutic effects of diverse small molecule drugs against coronaviruses for prophylaxis or treatment purposes and reduce viral titer by over four orders of magnitude. Using lipid nanoparticle-mediated RNA delivery, it has been demonstrated that the Cas13d system can effectively treat infection from multiple variants of coronavirus, including Omicron SARS-CoV-2, in human primary airway epithelium air-liquid interface (ALI) cultures. Recent studies establish CRISPR-Cas13 as a BSA which is highly complementary to existing vaccination and antiviral treatment strategies.
Vaccination is the act of getting a vaccine, usually in the form of an injection into the arm of a person (immunization) to protect against a disease. Testing for an effective vaccine is done in 3 phases from animals to humans to if it produces an immune response. if the vaccine protects against the coronavirus in at least 50% of vaccinated people it is considered effective and regulators decide whether to approve the vaccine or not. The mRNA vaccines (Pfizer and Moderna) proved highly effective at 95% and 94%, respectively, and received immediate EUA in January 2021.
Vaccination levels must produce a threshold called “herd immunity” to achieve “R-Naught” (RO) or SIR
(“susceptible-infectious-recovered” formulation), a factor that determines the transmissibility of the pathogen. It denotes the average number of secondary cases of an infectious disease that 1 case would generate in a completely susceptible population. That is, when one infected person infects greater than one other person, a potential exponential increase in infections results leading to an epidemic or pandemic. If, however, transmission on average remains below an RO of one person, this will result in a decreasing spread in infection and eventually into a majority of the population (an estimated 70% to 80% needed) to produce “herd immunity.” In the absence of a vaccine, developing herd immunity to an infectious agent requires large amounts of people actually being infected, developing antibodies to the infectious agent and thus becoming immunized against future infection. Assuming that immunity achieved (and long-lasting?), a very large number of people must be infected to reach the 70% to 80% herd immunity threshold required. During this process, mortality of certain infections like SARS-CoV-2 could reach unacceptable levels as occurred in Sweden where herd immunity was attempted. Nor does a pathogen magically disappear when the herd immunity threshold is reached. Rather, it only means that transmission begins to slow down and that a new epidemic is unlikely to start up again. An uncontrolled pandemic could continue for months after herd immunity is reached, potentially infecting many more millions in the process. These additional infections are what epidemiologists refer to as “overshoot.”
Researchers are genetically sequencing the entire human immune (the "immunome") system, a system billions of times larger than the human genome. The goal is to encode the genes (the antibody-encoding genes from Blog #7) responsible for circulating B cell receptors. This can provide potentially new antibody targets for vaccines and therapeutics that work across populations. The Human Vaccines Project seeks to define the genetic predisposition of people’s ability to respond and adapt to an immense range of diseases. The study specifically looks at one part of the adaptive immune system, the circulating B-cell receptors that are responsible for the production of antibodies, considered the primary determinant of immunity in people. The receptors form unique sequences of nucleotides (DNA base compounds) known as receptor “clonotypes.” This creates a small number of genes that can lead to an incredible diversity of receptors, allowing the immune system to recognize almost any new pathogen. This Project marks a crucial step toward understanding how the human immune system works, setting the stage for developing next-generation health products, drugs, and vaccines through the convergence of genomics and immune monitoring technologies with machine learning and artificial intelligence (AI).
The application of the knowledge from immunoinformatics (computational immunology) has led to a better understanding of the importance of the immune system through effective approaches like in silico immunoinformatics (scientific experimentation and research conducted or produced by means of computer modeling or computer simulation). For example, AI and immunoinformatics are being used to better understand the three-dimensional structure of proteins to determine their genetically encoded
amino acid sequence (Next-gen sequencing [NGS]). This structure influences the role and function of the protein involved in SARS-Cov-2 infection its most mRNA vaccine. An AI Google DeepMind system called AlphaFold uses amino acid sequencing and protein structure. This system has been applied to predict the structures of six proteins related to SARS-CoV-2.
In silico immunoinformatics depends on experimental science (“wet lab”) to produce raw data for analysis. It do not replace the traditional experimental research methods of actually testing hypotheses. The quality of immunoinformatics predictions depends on the quality of data and the sophistication of the algorithms being used (remember the old, "garbage in – garbage out" axiom). The future of immunological research will be enhanced by the ability to make discoveries in biologics (e.g., vaccines) more effectively and efficiently through combined AI and in silico immunoinformatics combined with traditional experimental research methods. Notwithstanding the credit certain narcissistic politicians like to take for the rapid development of COVID-19 vaccines, it was the combination of brilliant researchers, AI, and immunoinformatics that brought home the bacon in the desperate COVID-19 human crisis.
The world celebrated the newly discovered vaccines in early 2021 that began the mitigation and reversal of the COVID-19 pandemic. The suffering and ill effects of the novel coronavirus have been devastating to the world through its toll on lives and the crippling economic effects it has had on individuals and governments. Without a doubt the greatest appreciation must go researchers and scientific community who tirelessly worked to find the vaccines so desperately needed. Companies like Pfizer, Moderna, AstraZeneca, J&J and the governments of most industrialized countries prioritized vaccine development with little concerns for costs of such initiatives. And perhaps the greatest cheer should go to the contribution made by the immunology, genetic, and AI technologies that provided the research scientists the tools needed to accomplish their task in record time. Those achievements by the research and scientific community started many years ago with the early work of heroes in immunology (one more shout out to Dr. Fauci) and the genetic research mentioned throughout this book.
We must all be thankful for these accomplishments that have begun to reduce the human suffering and economic devastation brought upon the world from this COVID-19 pandemic. But we must also remain scrupulously vigilant. Today, the impact of COVID-19 and its rapidly evolving variants portend equal or more disastrous effects with the SARS-CoV-2 novel coronavirus being a far more contagious
member of the coronaviruses (CoVs). Many countries have relied on an extrapolation of classic infection-control and public-health measures similar to those used for SARS-CoV-1 to contain the COVID-19 pandemic. They range from extreme quarantine measures, “shelter-in-place,” “social distancing,” to painstaking detailed contact tracing with hundreds of contact tracers. However, these measures may not be effective in the coming years for tackling the scale of COVID-19. Healthcare systems should plan to use AI technologies and digital technology “virtual clinics” using telehealth consultations with imaging
data uploaded from peripheral sites and interpreted remotely. This would ensure that patients continue to receive standard clinical care while reducing physical crowding of patients into hospitals. Chatbots staffed by health professionals can also provide early diagnoses as well as patient education. And blockchain technologies can coordinate hospital, clinics, and pharmacy patient information.