COVID-19 Treatments and Vaccines: A year in Review

Abstract

The SARS-CoV-2 coronavirus (COVID-19) pandemic has precipitated an enormous collaborative global effort within the scientific and medical community in search of therapeutic and preventative solutions. The aim of this review is to collate the key developments regarding pharmacological treatments tested and vaccine candidates that have been approved to treat and arrest the spread of COVID-19. Introduction COVID-19 Transmission   The COVID-19 outbreak has caused one of the most widespread and significant public health crises in decades. It has become one of the leading causes of death internationally. The primary  route of transmission from person-to-person is from airborne aerosol spread through close physical  contact, particularly in enclosed, poorly ventilated areas.(1) Transmission through contaminated  objects was originally considered a major transmission contributor; however, it is no longer  considered a significant driver of the spread. Wearing masks has shown to be effective at  preventing or curtailing viral transmission, especially when combined with other measures like  social distancing and depopulation of indoor communal spaces.(2)  Mechanism of action: The mechanism of action and entry into human physiology at a cellular level has been described previously.(3) Briefly, the virus binds and enters the host cell through a spike  protein expressed on its surface. The infection begins when the long protruding spike proteins that latches on to the angiotensin-converting enzyme 2 (ACE-2), a receptor involved in regulating blood pressure ACE-2 protein. From this point, the spike transforms, unfolding and refolding itself, using coiled spring-like parts that start out buried at the core of the spike. The reconfigured spike hooks and docks the virus particle to the host cell. This forms a channel allowing the viral genetic material into the unsuspecting cell, in the case of COVID-19, type II lung cells. From this point onwards,  most of the damage caused by COVID-19 results from the immune system going into overdrive to  stop the virus from spreading.(4) The influx of immune cells to the infected tissue causes severe  damage in the process of cleaning out the virus, infected cells, and bacterial infections with  potentially lethal consequences.   Treatments   Medical therapies to treat COVI-19 evolved rapidly. Treatments include drugs that were approved by the US Food and Drug Administration (FDA) and drugs made available under FDA emergency use authorizations (EUA). The Centers for Disease Control and Prevention (CDC) has strongly encouraged clinicians, patients, and their advocates to consult the treatment guidelines published by the National Institute of Health (NIH). These guidelines are based on scientific evidence and expert opinion.(5) Several therapeutic modalities have been tested and deployed to treat the disease, some of which  are summarized here. Anti-virals: Antivirals are drugs that arrest the replication of the virus. They are generally considered most effective when administered in the early phase of infection. Remdesivir: To date, remdesivir is currently the only antiviral approved under EUA by the FDA to treat COVID-19. The approval was based on findings that hospitalized patients who receivedremdesivir recovered faster.(6)Remdesivir can be administered either alone or in combination with  other medications.   Molnupiravir: An antiviral drug, previously known as EIDD-2801, appears safe and effective. Viral levels reduce to undetectable levels in COVID-19 patients after five days of administration, according to data from a US-based Phase II clinical trial. While molnupiravir is proven to inhibit coronavirus replication in infected patients, more data is required to determine whether it can prevent severe illness.(7)  Lopinavir/ritonavir: Lopinavir/ritonavir are anti-human immunodeficiency virus (HIV) drugs. Both have been investigated and neither drug showed any efficacy in large randomized controlled trials in hospitalized COVID-19 patients.(8)   Anti-inflammatories: One reason for mortality in COVID-19 infected patients is an overactive response by the patient’s immune system. This response leads to several inflammatory disorders, not least of which is the much publicized “cytokine storm”. The following outlines agents have been tested to dampen the inflammatory response to COVID-19.   Dexamethasone: Dexamethasone is an anti-inflammatory corticosteroid used for many years to treat autoimmune conditions and allergic reactions. It is cheap and widely available and has been  shown to reduce mortality in the sickest hospitalized patients by dampening the immune  response.(9) A meta-analysis study evaluating the results of seven trials shows the death rates  were lower in hospitalized patients who took one of three different corticosteroids —  dexamethasone, hydrocortisone, or methylprednisolone.(6)  Baricitinib: Baricitinib is an anti-inflammatory drug used for the treatment of rheumatoid arthritis. In November 2020, the FDA issued an EUA to use baricitinib in combination with remdesivir in hospitalized adults and children two years and older requiring respiratory support. However, there is not enough evidence to support the use of this therapy with or without remdesivir.(10)  Antibody Based Treatments: Antibodies are proteins generated by the immune system to help fight infections, such as viruses, by binding to and destroying them. Antibody-based treatments are likely most helpful soon after infection, rather than after the disease has progressed.   Monoclonal antibodies: Monoclonal antibodies are synthesized in the laboratory. The FDA has  approved two monoclonal antibody treatments, one single antibody from Eli Lilly, and a  combination of two antibodies from Regeneron.   The Eli Lilly antibody, Bamlanivimab (LY-CoV555), works by blocking COVID-19 from entering and infecting human cells. Preliminary results indicated that patients with mild-to-moderate COVID-19 who received bamlanivimab were less likely to be hospitalized. Studies are still underway, both as a monotherapy and combination therapy. Regeneron’s treatment utilizes a combination of two monoclonal antibodies, casirivimab and imdevimab (REGN-COV2), referred to as an antibody cocktail. Preliminary trial data reported that REGN-COV2 reduced viral load and relieved symptoms sooner in non-hospitalized patients. These treatments are available for patients under EUAs, but more data is required before becoming part of routine care.(6)  Convalescent plasma: One of the first groups of antibody-based treatments used convalescent plasma (plasma from recovered COVID-19 patients). This treatment involves administering plasma from a recovered individual into someone infected with the virus. Theoretically, the antibodies fromthe recovered individual neutralize the virus in the infected individual. Although the FDA issued an EUA for convalescent plasma for hospitalized patients with COVID-19, the data to date has been conflicting and inconclusive.(6)  Anti-coagulants: Because of the systemic nature of COVID-19 where the circulatory system supplies all parts of the body, some COVID-19 deaths are believed to be caused by blood clots forming in major arteries and veins. A recent study has reported that full-dose blood thinners decreased the need for life support and improved outcome in hospitalized COVID-19 patients. (11) This worldwide large clinical trial, where full dose treatments were administered to moderately ill patients hospitalized for COVID-19, reduced the requirement of vital organ support—such as the need for ventilators.   In addition to some of the FDA approved drugs cited in the previous section, multiple treatments were investigated during the early phase of the COVID crisis, with varying results.(12) In contrast to  the overall trials for COVID-19 treatments, the programs initiated for vaccine development have  been incredibly successful, surpassing all expectations.   Vaccines   From the outset of the COVID-19 pandemic, vaccines ultimately offer the most appealing and robust therapeutic modality as they prevent the disease from taking hold. This has led to a global vaccine R&D effort that is unprecedented in terms of scale and delivery. The urgency to create a vaccine for COVID‑19 led to expedited schedules that compressed the standard vaccine development timeline from years to months.   At the time of writing, three vaccines have been authorized for emergency use by the FDA in the US, with more likely to come onstream as they progress through the development pipeline. A fourth vaccine, from Oxford-AstraZeneca, has also been approved for distribution within the European Union (EU). The three vaccines approved in the US are highly effective at preventing hospitalization, death, and severe disease. Vaccines work by triggering an immune response that generate highly specific antibodies against an antigen, in the case of COVID-19, the virus spike protein expressed on the surface of the virus. Moreover, the immune system is taught to recognize the spike protein specific to the virus. If this spike protein is encountered in the future, an immune response is swiftly mounted, thus preventing escalation of the virus.   Two of the authorized vaccines, developed by both Pfizer/BioNTech and Moderna, have revolutionized a technology referred to as messenger RNA (mRNA) technology. This technology acts as a delivery system to cells within our bodies with specific instructions to carry out a specific task.(13)  Of importance:   mRNA vaccines do not use live virus, but rather a portion of the message encoding for the  spike protein.   mRNA is produced by DNA, but does not enter the nucleus of the cell containing the DNA.  Once the mRNA vaccine finishes producing the protein that is expressed on the cell surface, it is broken down and removed by normal cellular processes.   The Johnson and Johnson (J