COVID-19 mRNA-Induced "Turbo Cancers"

Vaccination

Should women undergoing in vitro fertilization treatment or who are in the first trimester of pregnancy be vaccinated immediately against COVID-19

Updated International Society of Geriatric Oncology COVID-19 working group recommendations on COVID-19 vaccination among older adults with cancer

Safety of SARS-CoV-2 mRNA vaccines and effects of immunosuppressive drugs on adverse reactions in patients with rheumatic diseases

Closing the global vaccine equity gap: equitably distributed manufacturing

De Novo and Relapsing Glomerular Diseases After COVID-19 Vaccination: What Do We Know So Far?

COVID-19 vaccines in pregnancy.

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 cel

Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: A case series

Immunization Update 2021

Cytomegalovirus (CMV) is a common herpes virus that infects 60%–100% of adults and is one of the main causes of infection after organ transplantation.1 In transplant recipients, CMV infection may occur because of transmission from the transplanted organ, reactivation of latent infection, or primary infection in a seronegative host.2 In solid organ transplants, CMV infection is associated with poor short-term and long-term outcomes including allograft function and survival.3-5 There are several factors that can lead to an increased risk of CMV primary infection and reactivation, including intensity of immunosuppression, use of lymphocyte-depleting therapies, acute rejection, and advanced age in the donor or recipient. Human leukocyte antigen mismatch, or immunologic incompatibility between donor and recipient based on white blood cell and tissue surface proteins; concurrent infections (such as with herpes virus 6 or 7); and genetic polymorphisms are also major risks for CMV reactivation.2 Coronavirus disease 2019 (COVID-19) has impacted healthcare in an unprecedented way since its emergence in late 2019. Outcomes with COVID-19 infection are worse for solid organ transplant recipients compared with the general population.6 It is possible that COVID-19 vaccination may lead to immune dysregulation in some solid organ transplant recipients, thereby increasing risks for CMV reactivation.7 Here, we present 10 cases of CMV infection in solid organ transplant recipients shortly after COVID-19 mRNA vaccination. CASES Between March 1, 2021, and June 30, 2021, we identified 10 cases of CMV infection in solid organ transplant recipients within 45 d of COVID-19 mRNA vaccination as summarized in Table 1. Of these, 3 each were lung, heart, and kidney allograft recipients, whereas 1 was a dual heart-kidney allograft recipient. Ages ranged from 32 to 73 y. Indications for organ transplantation are available in the table. Two of the lung transplant recipients, 1 heart recipient, and 1 kidney recipient were CMV high-risk status (donor positive [D+]/recipient negative [R−]), whereas the others were recipient-seropositive (intermediate risk) for CMV. Median time to polymerase chain reaction (PCR) detection of CMV DNAemia from the second dose of mRNA vaccine was 15 d with a range of 4–44 d. The most recent transplant was a heart recipient transplanted 8 mo prior who had come off antiviral prophylaxis at 6 mo posttranplant, whereas the most remote transplant was a heart recipient transplanted 14 y prior. None of these recipients had posttransplant CMV infection detected previously. All patients were off antiviral prophylaxis either because of center or program protocol (available in Table S1, SDC, https://links.lww.com/TXD/A429) or because of intolerance of prophylactic medications due to cytopenias, and they were on their standard immunosuppressive regimen at the time of vaccination. Symptoms were variable but ranged from asymptomatic to acute respiratory and multiorgan failure. However, all patients had the resolution of CMV DNAemia by the censor date with a range of 7–58 d. Therapy included reduction of immunosuppression, intravenous ganciclovir, and oral valganciclovir. The median peak CMV DNA PCR in the cohort was 1792 IU/ml with a range of 272 to 3.11 million IU/ml. TABLE 1. - Summary of Solid Organ Transplant Recipients with CMV Reactivation after mRNA COVID-19 Vaccine Administration Case no. Vaccine Age, y Gender Type of transplant Primary disease Time since transplant Donor/recipient CMV status (±) Presenting symptoms Treatment Time to serum CMV DNA PCR <200, d CMV highest serum DNA PCR (IU/mL) 1 mRNA-1273 (Moderna) 63 M Right lung IPF 34 mo (±) Fever, dyspnea IV ganciclovir followed by oral valganciclovir 30 164 000 2 mRNA-1273 (Moderna) 70 F Right lung IPF 18 mo (±) Dyspnea, cough IV ganciclovir followed by oral valganciclovir 45 175 973 3 BNT162b2 (Pfizer)/mRNA-1273 (Moderna) 42 M Bilateral lung Bronchiectasis 22 mo (±) Dyspnea Oral valganciclovir 42 15 900 4 BNT162b2 (Pfizer) 73 M Heart and Kidney Ischemic cardiomyopathy 14 y (heart), 6 y (kidney) (±) Asymptomatic None 14 363 5 BNT162b2 (Pfizer) 53 M Heart Nonischemic cardiomyopathy 9 mo (±) Fatigue, exertional dyspnea Oral valganciclovir 16 272 6 mRNA-1273 (Moderna) 56 F Heart Nonischemic cardiomyopathy 8 mo (±) Asymptomatic IV ganciclovir followed by oral valganciclovir 16 3969 7 mRNA-1273 (Moderna) 67 M Heart Nonischemic cardiomyopathy 18 mo (+/+) Asymptomatic Oral valganciclovir 7 1792 8 BNT162b2 (Pfizer) 32 M Kidney IgA nephropathy 10 mo (+/+) Asymptomatic Oral valganciclovir 11 755 9 BNT162b2 (Pfizer) 60 M Kidney HIV nephropathy 14 mo (+/+) Asymptomatic Oral valganciclovir 15 1285 10 BNT162b2 (Pfizer) 73 M Kidney Diabetic nephropathy 18 mo (±) Weakness IV ganciclovir followed by oral valganciclovir 58 3 110 000 Case no. Prior CMV infection COVID antibody CMV disease state Admission leukocyte count Admission absolute lymphocyte count Immunosuppression Cessation of prophylaxis mo/y before first CMV vaccine Episode of Rejection y/n after vaccination Time from last episode of rejection to + CMV PCR(rejection grade) Time from COVID-19 vaccination second dose to + CMV PCR, d 1 No Negative CMV pneumonitis 2 1.04 Tacrolimus, Mycophenolate 500 mg BID, Prednisone 5 mg 2 mo N 2 y 6 mo (A2B0) 16 2 No Negative CMV pneumonitis 5 0.88 Prednisone 10 mgTacrolimus 2 mo N 1 y 2 mo (A2B0) 5 3 No Negative CMV Viremia 4 1 Tacrolimus, Mycophenolate 500 mg BID, Prednisone 10 mg 3 mo N 1 y 9 mo (A2B2R) 4 4 No Negative CMV Viremia 5.4 1.35 Tacrolimus, Mycophenolate 500 mg BID, Prednisone 5 mg 4 y N 4 y (ACR 2016) 30 5 No Negative CMV Pneumonitis 8.3 1.01 Tacrolimus, Mycophenolate 500 mg BID, Prednisone 5 mg 4 mo N 6 mo (ACR 2R) 14 6 No Negative CMV Viremia 5.1 2.59 Tacrolimus, Mycophenolate 250 mg BID, Prednisone 5 mg 2 mo N N/A 24 7 No Negative CMV Viremia 4.9 0.5 Tacrolimus, Mycophenolate 500 TID 2 mo N N/A 16 8 No Negative CMV Viremia 6.3 0.59 Tacrolimus, Mycophenolate 250 TID 4 mo N N/A 44 9 No Negative CMV Viremia 3 1.02 Tacrolimus, Mycophenolate 250 mg BID, Prednisone 10 mg 3 mo N 6 mo (1B) 15 10 No Negative CMV Viremia 5.2 0.67 Tacrolimus, Prednisone 10 mg 7 mo N N/A 18 BID, twice a day; CMV, cytomegalovirus; F, female; Ig, immunoglobulin; IPF, idiopathic pulmonary fibrosis; IV, intravenous; M, male; PCR, polymerase chain reaction; TID, three times a day.Case 3 received the 2-dose BNT162b2 vaccine series 8 wk before starting the 2-dose mRNA-1273 series; the reported positive CMV PCR resulted 4 d after completing the mRNA-1273 series. Three patients received the mRNA-1273 (Moderna) vaccine, whereas the remainder received the BNT162b2 (Pfizer) vaccine. None of the recipients developed immunoglobulin G antibodies to SARS-CoV-2 in response to vaccination. There were no documented cases of COVID-19 in these transplant recipients. The first identified and representative patient was a 63-y-old man with idiopathic pulmonary fibrosis who underwent right lung transplant (D+/R−) 3 y before COVID-19 vaccination and had been clinically well. His prophylactic valganciclovir was stopped 24 mo after transplant per institutional protocol. After the second dose of the mRNA-1273 vaccine, he developed generalized malaise and a slightly elevated temperature of 37.2 °C (99 °F). Sixteen days after his second vaccine dose, he presented to the emergency department with dyspnea and acute hypoxemia. He underwent bronchoscopy with transbronchial biopsies which demonstrated CMV pneumonitis with no evidence of acute cellular rejection. His admission blood CMV DNA PCR was 164 000 IU/ml. Treatment with intravenous ganciclovir reduced the CMV DNAemia to 69 000 IU/ml within a week. Reduction in CMV viral load was accompanied by clinical improvement. One week after discharge, he required readmission with worsening respiratory failure requiring mechanical ventilation. His CMV PCR was 707 IU/ml, and he was treated for presumed acute cellular rejection with high-dose intravenous corticosteroids with eventual liberation from mechanical ventilation. Two weeks after the second discharge, his blood CMV PCR was <200 IU/ml, and he was transitioned from intravenous ganciclovir to oral valganciclovir. A second representative case is a 73-y-old man who underwent deceased donor kidney transplantation (D+/R−) the year before vaccination for end-stage renal disease due to diabetes. The patient had an uncomplicated surgical recovery and was clinically well. Two weeks after the second dose of the BNT162b2 vaccine, he presented to the emergency department with generalized weakness, fatigue, hypotension, and elevated serum creatinine (1.6 mg/dL from baseline of 1.1 mg/dL). Blood CMV PCR was 3.11 million IU/mL. He was treated with intravenous ganciclovir with reduction in CMV DNAemia to 41 000 IU/mL after 3 wk. He was transitioned to oral valganciclovir and his blood CMV PCR was 415 IU/mL 1 wk later. The patient remains on prophylactic valganciclovir with undetectable blood CMV DNA PCR. DISCUSSION We present 10 cases of CMV DNAemia after COVID-19 mRNA vaccination in solid organ transplant recipients; a phenomenon we believe is underrecognized. Overall, CMV reactivation after vaccination in solid organ transplant recipients appears to be very rare, and to our knowledge there is only 1 published report of 2 cases of CMV DNAemia viremia in kidney transplant recipients after receiving an inactivated influenza vaccine.8 Our case series is the first to describe CMV DNAemia after COVID-19 vaccination in solid organ transplant recipients. By virtue of its observational nature, our study is unable to draw a causal association between vaccination and CMV infections. However, all cases of CMV DNAemia described in our case series occurred in close temporal relation to patients receiving either the mRNA-1273 or BNT162b2 COVID-19 mRNA vaccines supporting a strong possible role. Notably, all the patients included in this series were not on CMV prophylaxis for at least 2 mo before COVID-19 vaccination (Table 1), with 6 of the 10 patients having had their prophylaxis stopped 3 mo or fewer before vaccination, suggesting these patients were in the high-risk period for reactivation or late CMV infection when they were vaccinated. However, none of these patients had CMV infections between the end of prophylaxis and the occurrence of CMV DNAemia after vaccination. Also, there was no rejection diagnosed in the 2 mo before CMV DNAemia, and thus augmentation of immunosuppression was not a contributing factor to CMV reactivation. Although the risk–benefit assessment strongly favors COVID-19 vaccination in solid organ transplant recipients,9,10 care teams should consider active monitoring for CMV disease activity in these patients. In some cases, CMV prophylaxis may be warranted depending on patients' risk profiles. Potential causes of CMV infection following COVID-19 mRNA vaccination may include "immune senescence" or dysregulation of the immune system.7-12 As patients with latent CMV age, more of their T-cell pool is directed toward keeping CMV latent. Thus, when faced with a novel virus like SARS-CoV-2, the immune system may be unable to appropriately expand the naïve T-cell pool and develop an adequate immune response13 without compromising immunity geared toward keeping CMV at bay. When patients receive an mRNA vaccine, the T-cell pool may be redirected toward the COVID-19 spike protein and away from CMV suppression. Another hypothesis is that the spike protein itself causes immune activation, thus leading to CMV reactivation. Others have suggested that about 25% of mRNA-vaccinated individuals have circulating spike proteins in their blood upwards of 1 mo after vaccination. As the spike protein is known to drive an inflammatory response, in immunosuppressed folks this phenomenon may drive virus reactivation.14 Regardless, awareness of this phenomenon is crucial to the management of these patients because of both short- and long-term deleterious consequences of CMV infection. CMV disease in transplant recipients often requires treatment, sometimes with hospitalization, and carries a risk for chronic allograft dysfunction.15-17 Moreover, the mortality rate of primary CMV infection 1 y after thoracic organ transplant may be as high as 54%.18 Although the majority of kidney transplant CMV infections tend to be asymptomatic, they may still result in significant morbidity and mortality.19 Moreover, treatment of CMV disease can be challenging. CONCLUSION CMV infection after COVID-19 vaccination in solid organ transplant recipients may be an underappreciated phenomenon; the risk seems to be highest in the population of patients who recently had their prophylaxis discontinued. Clearly, the risk–benefit assessment strongly favors COVID-19 vaccination for solid organ recipients. However, an increased awareness of a potentially associated risk of CMV reactivation may help care teams to more rapidly diagnose and manage this complication or perhaps consider short-term reinstitution of viral prophylaxis around the time of vaccination.

The COVID-19 Pandemic in 2021: Avoiding Overdiagnosis of Anaphylaxis Risk While Safely Vaccinating the World

By May 15, 2020, 65 days after the World Health Organization (WHO) declared the novel coronavirus disease 2019 (COVID-19) pandemic, 4.2 million individuals were confirmed as being infected with the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and 294,000 people had died from the disease1. These numbers are almost certainly an underestimation of the true morbidity and mortality of the disease to this point. From the beginning of this public health crisis, attention has focused on the development of vaccines against SARS-CoV-2. Many believe that immunization is the key advance in the war against COVID-19 and that control of SARS-CoV-2 allowing approximations of pre-pandemic social conditions will not be possible without a viable vaccine2. Until a viable vaccine is developed, extensive diagnostic testing, quarantining, and social distancing are the only control methods that we have3. This article was written for musculoskeletal physicians and scientists without immunology backgrounds. It seeks to provide a concise but comprehensive understanding of vaccine development with a special emphasis on efforts to establish immunization directed against SARS-CoV-2. This will help to inform readers of the challenges to be hurdled and allow them to track milestones reached as the global community labors toward an effective vaccine. In-depth reviews of complex immunology topics, viral epidemiology, the myriad historic aspects of vaccine development, and the economics of developing and utilizing different types of vaccines are beyond the scope of this work. Background SARS-CoV-2 To understand the process of vaccine development, one must start with a basic understanding of the pathogen against which it will be directed. SARS-CoV-2 is a beta coronavirus4. The virus has been found to be similar to another coronavirus whose usual hosts are bats. It is believed that wild animals being sold at a market in Wuhan, Hubei Province, the People's Republic of China, led to the transmission of SARS-CoV-2 to humans5. Members of the Coronaviridae family have a positive-sense, single-stranded RNA ([+]ssRNA) genome6. The (+)ssRNA can serve as messenger RNA (mRNA) in the host cell, allowing utilization of host ribosomal machinery to translate viral proteins. This coronavirus genome is highly conserved6. The first gene (open reading frame [ORF]1a and ORF1b) is involved in replication and transcription. Subsequent genes are related to structural proteins (Fig. 1). The spike protein (S) has an exposed location on the virion and is necessary for entry into the cell. Blocking of the spike protein epitopes that interact with angiotensin-converting enzyme 2 (ACE2), the host cellular receptor for SARS-CoV-2, should lead to neutralization (Fig. 2). ACE2 degrades angiotensin II (AngII), downregulating the renin-angiotensin-aldosterone system. ACE2 is distinct from the angiotensin type-I receptor, which leads to activating signal transduction by AngII7.Fig. 1: Illustration of the SARS-CoV-2 genome showing expressed structural component proteins and their location within the virion. The open reading frame (ORF) codes for nonstructural viral proteins participating in viral genome replication, transcription, and protein processing. The spike protein (S) binds to the ACE2 receptor, allowing virus entry into host cells. The envelope protein (E) has been found to bind to host gene regulatory proteins and putatively influences host cell gene expression. The membrane protein (M) seems to cooperate with S during binding and entry into the cell. The nucleocapsid protein (N) coils the viral mRNA inside the viral particle, organizing and protecting it.Fig. 2: SARS-CoV-2 virion entry into the host cell. The virus enters the host cell via the S protein interacting with ACE2. It is important to generate antibodies to the S protein rather than ACE2. This allows ACE2 to remain open to receive the host ligand and to avoid the possibility that the blocking antibody interferes with its normal physiologic function.COVID-19 is usually characterized by fever, cough, dyspnea, fatigue, and sore throat. Radiographic findings have demonstrated pneumonia with infiltrates on chest imaging8. Typically, radiographic changes appear on presentation. In Wuhan, 76% of diagnosed patients demonstrated changes on chest radiographs9. It is unknown whether radiographic changes arise prior to the onset of symptoms. Currently, there are no known curative treatments for COVID-19. Treatment is centered around supportive care while the afflicted individual clears the infection. In some cases, supplemental oxygen needs to be administered to help those with the associated pneumonia to maintain their oxygen saturation. Severe cases may benefit from antiviral medications, dexamethasone10, and ventilatory support with or without extracorporeal membrane oxygenation11,12. In March 2020, the WHO estimated the global mortality rate for those confirmed to have a SARS-CoV-2 infection to be 4.3%, although this varies by region13. Vaccines Vaccines meet the definition of a drug because they are substances other than food used in the prevention, diagnosis, alleviation, treatment, or cure of a disease14. They are administered to healthy individuals to prevent diseases caused by infectious agents to which they might be exposed in the future or, in some cases, to which they have been recently exposed. Immunization is the process of presenting antigens to a live host to induce an immune response. Vaccines can be utilized therapeutically and prophylactically. Most vaccines are developed as prophylaxis against infection. A primary goal of prophylaxis is to generate neutralizing antibodies that prevent viral entry into cells. However, in some cases, vaccines can be administered for short-term protection. This short-term protection is termed passive immunization. A smaller proportion of vaccines are developed for the therapeutic treatment of infections that have already become initiated. An example of this is the vaccine used after exposure to rabies15. Epidemiology of Infectious Disease and Vaccination During infectious disease outbreaks, vaccines have the ability to break chains of transmission, drastically slowing the propagation of infection and eventually eradicating the disease. The vast majority of individuals in modernized societies are immunized against a host of pathogens as children. This global public health effort has resulted in the worldwide elimination of smallpox16 and substantial progress toward the elimination of polio17. These accomplishments required concerted international efforts that were sustained over many decades. The epidemiologic dynamics of vaccination, especially in a population with a disease presence (either endemic or epidemic), can be described mathematically. The basic reproduction number (R0) is the intrinsic measure of transmissibility of a pathogen. It describes the mean number of secondary infections resulting from a single infection within a fully susceptible population (Fig. 3). For SARS-CoV-2, R0 has been estimated to be between 2 and 318.Fig. 3: Illustration of the basic reproduction number (R0) values for representative infectious diseases, demonstrating increasing infectivity with increasing values of R0. HIV = human immunodeficiency virus.Once substantial immunity, through either vaccination or natural exposure to the disease, starts to be established in the population, R0 becomes a less accurate measure of transmissibility, and a second number, the effective reproduction number (Re), becomes more representative of transmissibility. Re represents the actual number of transmissions per infection. For an explanation of how these numbers are calculated and their effect on viral epidemiology (Fig. 4), please see Appendix I.Fig. 4: The relationship between the basic reproduction number (R0) and the effective reproduction number (Re) of a pathogen. Re changes based on the percentage of the population that is immune, demonstrated by the different lines on the chart. For a disease with an R0 of 3.5, immunization of 70% of the population will be necessary to bring Re below 1.0. This can be compared with an immunization level of only 50% needed to bring Re below 1.0 for a disease with an R0 of 2.0. If Re, a measure of disease transmissibility, is <1, a disease outbreak will end without further measures being taken.Herd Immunity Herd immunity is a condition achieved in a population when the indirect protection of susceptible individuals against a specific pathogen is conferred by immune individuals. In effect, those with immunity within a population shield those without immunity from transmission, thereby limiting the spread of the disease19 (Fig. 5). A further explanation of how R0 and Re affect herd immunity (Figs. 6 and 7) is found in Appendix II.Fig. 5: Illustration demonstrating herd immunity. The spread of a hypothetical illness within a population is shown under 3 different conditions. The top row is a time early after the introduction of the pathogen within a population. The second row represents 1 replication cycle and the third row represents 2 replication cycles following the time represented in the top row. In the left column, the population is fully susceptible (no naturally acquired immunity or immunity through vaccination) to the pathogen. The middle column represents an intermediate state between full susceptibility and achievement of the herd immunity threshold (Pcrit). The column on the right represents how spread is hindered in a population that has already achieved Pcrit.Fig. 6: The relationship between the basic reproduction number of a virus, R0, and the proportion of the population that needs to be immunized to enter into a state in which herd immunity takes effect, Pcrit. R0 is unitless and Pcrit is measured as the percentage of the population. The slope of the curve is greatest between R0 values of 1 and 4, indicating that a large increase in the proportion of immune individuals within the population is needed to achieve Pcrit for an infectious disease with an R0 that is just slightly larger than another. The estimated R0 for SARS-CoV-2 is between 2 and 3, which is demarcated in the area between the dotted lines on the graph. This R0 range indicates that the percentage of the population that needs to become immune to reach Pcrit, either through infection or vaccination, is between 50% and 66.7%.Fig. 7: Vaccination affects the achievement of herd immunity. This graph shows vaccination affecting herd immunity to diphtheria. Diphtheria-tetanus-pertussis (DTP3) immunization coverage is expressed as a percentage of the population from 1982 to 2016. The red line on this graph represents the number of diphtheria cases reported worldwide by year. The blue line represents the immunization coverage as a percentage of the population by year. The dashed orange line represents the herd immunity threshold (Pcrit) for diphtheria assuming that it has an R0 of 6. The graph demonstrates how achieving immunization levels just slightly above Pcrit can drive the number of cases down to just a few thousand per year.SARS-CoV-2 Vaccines Under Development It is through recombinant nucleic acid technology that most efforts against COVID-19 are progressing. Theoretically, vaccines using recombinant nucleic acid technology can be developed and, therefore, deployed more quickly than those using more traditional means. However, a few are based on immunologic techniques used widely in the mid-twentieth century for the development of vaccines used in standard childhood immunization schedules. Table I summarizes the types of vaccines as well as their advantages and disadvantages. By June 2, 2020, >130 candidate vaccines targeting SARS-CoV-2 were under development worldwide according to the WHO20. Ten of these candidate vaccines have entered into human trials. Table II summarizes the SARS-CoV-2 vaccines currently in development. TABLE I - Advantages and Disadvantages of Different Vaccine Types* Type of Vaccine Example Vaccine(s) Advantages Disadvantages Potential Solutions to Development Problems Attenuated Sabin polio (host-range mutant) Smallpox (Jennerian method) Reliable Confer both humoral and cell-mediated immunity Limited need for booster doses Relatively inexpensive technology May yield less protective mutant viruses if passages are performed in non-human cell lines63 Can cause disease in immunocompromised individuals Enhanced storage and maintenance requirements (e.g., refrigeration, culture media) Inactivated Typhoid Salk polio Rabies Influenza Relatively fast Easy to scale up Relatively inexpensive development Alternate routes of administration (e.g., oral) Inactivation can sometimes damage key epitopes Can still theoretically cause disease (if not fully inactivated) Labor-intensive process to ensure no viable virion remains after inactivation Greater amounts of inoculum required to achieve immunity Immune response is less durable, requiring booster doses64 Titration of inactivation methods to prevent overtreatment, maintaining key epitopes Subunit Hepatitis B surface antigen Safe Easy to use Requires large amounts of isolated antigen Immunopotentiation2,65 Recombinant technology has made large-scale production possible Adjuvants can be added to vaccine preparations66 mRNA29 HIV† Zika† Influenza† Rabies† Can replicate using host machinery Highly potent Relatively fast Easy to scale up • Relative low cost of manufacturing Safe Confer both humoral and cell-mediated immunity dsRNA byproducts of production are PAMPs‡ and lead to immune recognition and degradation29 Inefficient delivery to target cells Instability of mRNA Modified nucleosides avoid host immune recognition Purification to eliminate dsRNA Multiple delivery methods devised to improve efficiency Inclusion of upstream and downstream untranslated sequences improves stability of mRNA DNA plasmid Prostate cancer† Melanoma† Can replicate using host machinery Highly potent Relatively fast Easy to scale up • Safe Confer both humoral and cell-mediated immunity Inefficient delivery to target cells Coupled treatments (e.g., electroporation) to improve DNA plasmid entry into human cells34 and enhance immune response32–33- Vector-based recombinant (e.g., adenovirus vector) Malaria† HIV† Ebola (in development) Confer both humoral and cell-mediated immunity Enter host cells via ubiquitously expressed cell surface receptors Can incorporate additional transgenes for biological adjuvants37,67 Highly potent Relatively fast Easy to scale up in low-resource settings68 Safe Easier, alternate routes of administration favoring IgA production (e.g., oral, intranasal)69,70 Vector immunity due to host recognition of adenovirus71 If replication-competent viral vectors are utilized, could cause adenovirus infection Administration via mucosa may require dose escalation Repeated immunizations can diminish neutralizing antibodies to adenovirus vectors, thereby decreasing vector immunity71 Utilize different adenovirus strains to evade vector immunity70,72,73 Utilize chimpanzee adenovirus vectors to evade vector immunity due to highly conserved genome74 Use of replication-competent viral vectors can boost immunogenicity *HIV = human immunodeficiency virus, dsRNA = double-stranded RNA, PAMP = pathogen-associated molecular pattern, and IgA = immunoglobulin A.†In trials.‡These are present and invariant in the pathogen but not in the potential host organism; PAMPs allow early recognition and immune activation by the host organism75. TABLE II - SARS-CoV-2 Candidate Vaccines Currently in Clinical Development* Vaccine Type Clinical Phase of Development Trial No. (Location) Chimpanzee adenovirus vector-based (nonreplicating) Phase 2b/3 2020-001228-32 (EU) mRNA (lipid nanoparticle encapsulated) Phase 2: scheduled to conclude September 2021 NCT04405076 (USA) Adenovirus-5 vector-based (nonreplicating) Phase 2: scheduled to conclude January 2021 ChiCTR2000031781 (China) Subunit (recombinant spike protein) Phase 1 and 2: scheduled to conclude July 2021 NCT04368988 (USA) mRNA (lipid nanoparticle encapsulated) Phase 1 and 2: scheduled to conclude June 2021 NCT04368728 (USA), 2020-001038-36 (EU) Inactivated with aluminum adjuvant Phase 1 and 2: scheduled to conclude July/August 2020 NCT04383574 (USA), NCT04352608 (USA) Inactivated Phase 1 and 2: scheduled to conclude November 2021 ChiCTR2000031809 (China) Inactivated Phase 1 and 2: scheduled to conclude November 2021 ChiCTR2000032459 (China) DNA plasmid (with electroporation) Phase 1: scheduled to conclude July 2021 NCT04336410 (USA) Inactivated Phase 1 China *As of June 2, 2020. Attenuated Vaccines Vaccines that use a weakened but viable form of the pathogen to establish an immune response are termed attenuated vaccines. The establishment of attenuated strains is an empiric rather than a designed process, the duration of which is influenced by the scale of the process and the time necessary to complete the passage of the virus in the cell culture. In rare cases, the attenuated variant can revert to a virulent form, resulting in the establishment of the disease in the immunized cohort. There are 4 different types of attenuated vaccines. At least 3 different groups are seeking to develop attenuated vaccines against COVID-1920. The most common form of an attenuated vaccine is the host range mutant. This type is usually achieved by the passage of the virus in the cell culture to generate nonvirulent mutants. Over multiple passages, the host range mutant acquires mutations, rendering it harmless while retaining the necessary antigens to generate immunity. The second type is naturally attenuated. This method requires empiric identification and recovery of variant or minimally variant strains during periods of outbreak21. The third type of attenuated vaccine is the temperature-sensitive mutant. This method isolates mutants that at of strains that can be at is the found at the respiratory but become nonvirulent at the or The type of attenuated termed is not being in the COVID-19 vaccine development Inactivated Vaccine vaccine requires large amounts of viral to be in and by either or (Fig. The of inactivation is to the virus nonvirulent without the epitopes to which an immune response is and can virus A needs to be achieved in the of vaccines. will lead to and of key to a neutralizing antibody response that is and protective with a live However, if complete inactivation not of the disease can from the vaccination through some vaccine types that are being developed against SARS-CoV-2. Inactivated viral are in and through or means. The of viral allows the of an immune response without of infection. Subunit viral proteins are and These proteins are into patients to be The proteins are by the host cells and the antigens are that an antibody response is mRNA mRNA the viral S protein is in the and is using technology as These mRNA are and are into viral proteins using host and the antigens are that an antibody response is DNA plasmid DNA for the viral S protein is into a DNA This plasmid enters host and machinery viral proteins. These viral proteins generate an antibody response. vector-based the gene for the viral S protein is into an adenovirus genome in These adenovirus vectors with entry into the host cell and the host machinery to viral proteins that generate an antibody Vaccines Subunit vaccines generate immunity by administration of a virus antigen (Fig. These antigens are by the immune to generate an antibody response. Typically, antigens are that will generate an immune response. For SARS-CoV-2, one of the candidate antigens for vaccine development is the spike A number of the of and are on developing spike protein mRNA Vaccines In this mRNA for the SARS-CoV-2 spike protein is into the host cells to it (Fig. proteins made by host cells will be as by the immune which will generate both an antibody and the response to mRNA vaccines have had that effective but have of these mRNA vaccine delivery and the of the and methods are standard at this 1 developing an mRNA vaccine against SARS-CoV-2 has that it could be as an measure to as early as DNA Vaccine the of the of SARS-CoV-2, the development of a DNA vaccine the (+)ssRNA genome of SARS-CoV-2, DNA sequences can be These sequences can be into or double-stranded DNA that for antigen DNA (Fig. can replicate using host is into host it can viral antigens that are as the host immune to generate an antibody and the response. This method of vaccine development advantages similar to those for mRNA vaccines nucleic are that the potential with protein which can recombinant multiple have demonstrated that can enter host cells and can in a immune This technology has been shown to be and in to there have been no DNA vaccines for use in Recombinant Vaccines Recombinant viral vectors have been as vaccine over the few for their ability to antigens and their immunogenicity (Fig. are DNA of recombinant adenovirus vector-based vaccines is that they can be made and highly effective through recombinant The of recombinant adenovirus vector-based vaccines is by rendering the virion replication This is achieved by the antigen in the of the adenovirus genome for viral replication, thereby its ability to most vaccines are administered either or adenovirus vector-based vaccines provide the possibility of This is a more administration than For these many different recombinant adenovirus vector-based vaccines targeting SARS-CoV-2 are currently under development. Immunization immunization may be achieved by administration of to a or recently infected protection against pathogens within the immunized The protective of the are eventually down or this the protective effect is because not or the immune to provide immunization. There are with and patients develop the at a of infection. Currently, there are a number of for the treatment of patients with Immunity to COVID-19 There and should a to develop a vaccine against SARS-CoV-2. health measures will need to the development, and administration of a vaccine against SARS-CoV-2 to a large proportion of the population. with these morbidity and mortality will The potential rate increase from to between and of the population while the the herd immunity threshold (Pcrit) may be to A number of potential immunity, immunity, and vaccine could the of a COVID-19 vaccine TABLE - and the of COVID-19 Vaccine Immunization on COVID-19 Vaccine Immunization immunity are of Immunity in individuals may require vaccination individuals may not be fully immune Vaccine is only effective May require vaccination or vaccination of more individuals than Pcrit Vaccine or use of vaccines to achieve Pcrit for development for vaccine development and is 4 the development can only if necessary the first Vaccine takes to develop similar efforts have of vaccine development, we still not have a vaccine Vaccine takes to develop molecular techniques more effective of recombinant Development Vaccines or manufacturing complete of vaccine development to from and Over worldwide on vaccine Development Vaccine to by the is especially A by the for that of not and were if they when a vaccine becomes A of found that were at and an additional were in a COVID-19 is an that could Pcrit or lead to the of COVID-19 The COVID-19 vaccine will not be the This was with polio and both of which through in the and types that were used when or were in the early The vaccines which groups to they are administered and toward and their delivery methods will with limiting vaccine is immunity. illness are of the This that SARS-CoV-2 may exposed individuals. may be due to either antibody and cell or The need for vaccination could the establishment of Pcrit. possibility is that only some individuals have full immunity. immunity is still it the numbers of infected individuals and those requiring care on the level of an care The of developed vaccines will most be by of blocking Vaccines that have entered into have already been for blocking antibodies in their The administration of different vaccines has been in achieving immunity. attenuated and polio vaccines administered have a for viruses with substantial as immunizations help to neutralizing antibody for conserved There is a complex of and on immune In antibody to vaccines are in while both humoral immune to novel that are related to multiple affect the time for immunity to a is 2 to 3 following the Problems that are of in developing a vaccine to RNA viruses are the of and is the of the viral disease rather than its This has led to and in immunized has been with a number of those against is the of infection. of infection when viruses are by cells via their or This has been shown to in human cells with It is not that vaccine administration will have a musculoskeletal However, the time to testing, and will have for the and of care It is standard methods or will be during the production and of viable as many of the currently being used have resulted in doses at that multiple vaccines and their will be to more and effective and administration to the Immunization with candidate vaccines should not lead to should be to allow the establishment of an immune response and of severe morbidity and mortality associated with The for the development of effective vaccines should be with the that the to achieve will be There will be many and we must to this The protective measures that we have social protective and the use of testing, will be a of COVID-19 has morbidity and Pcrit will be in to a of social Pcrit will be through immunization. an early and response toward developing a COVID-19 remain in Recombinant techniques may this A between the community and should the need for vaccine development with Appendix by the is with the of this article as a at

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