Review of COVID-19 viral vector-based vaccines and COVID-19 variants.

The concept of viral vector-based vaccine was introduced in 1972 by Jackson et al and in 1982 Moss et al introduced the use of vaccinia virus as a transient gene expression vector. The technology has been used to make Ebola vaccines and now COVID-19 vaccines. There are two types of viral vector-based vaccines i.e. replicating and non-replicating. Non-replicating viral vector-based vaccines use replication-deficient viral vectors to deliver genetic material of a particular antigen to the host cell to induce immunity against the desired antigen. Replicating vector vaccines produce new viral particles in the cells they enter, which then go on to enter more new cells which will also make the vaccine antigen. Non-replicating vector-based vaccines are more commonly utilized. Adenovirus, vesicular stomatitis virus, vaccinia virus, adenovirus associated virus, retrovirus, lentivirus, cytomegalovirus, and sendai virus have been used as vectors. Current adenovirus vector-based vaccines being administered against SARS-CoV-2 infection are JNJ-78435735 by Johnson and Johnson (Janssen) along with Beth Israel Deaconess Medical Center, AZD1222 by Oxford-AstraZeneca, Sputnik V and Sputnik Light by Gamaleya Research Institute of Epidemiology and Microbiology, and Convidecia vaccine by CanSino Biologics. Of the five vaccines, the United States Food and Drug Administration (FDA) has approved Janssen vaccine for emergency use. Efficacy against COVID-19 variants has been found in all but the Convidecia vaccine so far. Heterologous prime-boost COVID-19 vaccination regimen may be the new face and more efficient immunization approach for enhanced immunity against COVID-19.

Review of COVID-19 Variants and COVID-19 Vaccine Efficacy: What the Clinician Should Know?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta coronavirus that belongs to the Coronaviridae family. SARS-CoV-2 is an enveloped spherical-shaped virus. The ribonucleic acid (RNA) is oriented in a 5'-3'direction which makes it a positive sense RNA virus, and the RNA can be read directly as a messenger RNA. The nonstructural protein 14 (nsp14) has proofreading activity which allows the rate of mutations to stay low. A change in the genetic sequence is called a mutation. Genomes that differ from each other in genetic sequence are called variants. Variants are the result of mutations but differ from each other by one or more mutations. When a phenotypic difference is demonstrated among the variants, they are called strains. Viruses constantly change in two different ways, antigenic drift and antigenic shift. SARS-CoV-2 genome is also prone to various mutations that led to antigenic drift resulting in escape from immune recognition. The Center of Disease Control and Prevention (CDC) updates the variant strains in the different classes. The classes are variant of interest, variant of concern and variant of high consequence. The current variants included in the variant of interest by the USA are: B.1.526, B.1.525, and P.2; and those included in the variant of concern by the USA are B.1.1.7, P.1, B.1.351, B.1.427, and B.1.429. The double and triple mutant variants first reported in India have resulted in a massive increase in the number of cases. Emerging variants not only result in increased transmissibility, morbidity and mortality, but also have the ability to evade detection by existing or currently available diagnostic tests, which can potentially delay the diagnosis and treatment, exhibit decreased susceptibility to treatment including antivirals, monoclonal antibodies and convalescent plasma, possess the ability to cause reinfection in previously infected and recovered individuals, and vaccine breakthrough cases in fully vaccinated individuals. Hence, continuation of precautionary measures, genomic surveillance and vaccination plays an important role in the prevention of spread, early identification of variants, prevention of mutations and viral replication, respectively.

Medically underserved areas and International Medical Graduates (IMGs) in the United States: challenges during the COVID-19 era.

Background: Given that nearly a quarter of the US physician workforce are international medical graduates (IMGs), many of whom remain on temporary work visas for prolonged periods due to processing delays, the pandemic has posed unique challenges to these frontline workers and has arbitrarily limited our physician workforce. Methods: This is cross-sectional survey data obtained from IMGs on temporary work visas pertaining to their role in healthcare, impact of visa-related restrictions on their professional and personal lives was sent to the participants. Results: A total of 2630 IMGs responded to the survey. Most of the respondents (1493, 56.8%) were physicians in active practice, with Internal Medicine (1684, 65.7%) being the predominant specialty encountered. 64.1% were practicing in Medically Underserved Areas (MUA) or Health Professional Shortage Areas (HPSA), with 45.6% practicing in a rural area. Nearly 89% of respondents had been involved with direct care of COVID-19 patients, with 63.7% assuming administrative responsibilities for COVID-19 preparedness. 261 physicians (11.5%) were subject to quarantine, while 28 (1.2%) reported a confirmed COVID-19 infection. 93% physicians expressed inability to serve in COVID-19 surge areas due to visa-related restrictions, while 57% had been approached by recruiters due to staffing shortages. 72% physicians reported that their families would be at risk for deportation in case of their disability or death. Most respondents (98.8%) felt that permanent resident status would help alleviate the above concerns. Conclusion: A significant proportion of the US physician workforce is adversely impacted by work-based visa restrictions and processing backlog. Mitigating these restrictions could significantly bolster the current physician workforce and prove beneficial in our response to the COVID-19 pandemic.

Review of COVID-19 Vaccines Approved in the United States of America for Emergency Use.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus causing a global pandemic. Coronaviruses are a large family of single-stranded ribonucleic acid (RNA) viruses. The virus has four essential structural proteins which include the spike (S) glycoprotein, matrix (M) protein, nucleocapsid (N) protein and small envelope (E) protein. Different technologies are being used for vaccine development to battle the pandemic. There are messenger ribonucleic acid (mRNA)-based vaccines, deoxyribonucleic acid (DNA) vaccines, inactivated viral vaccines, live attenuated vaccines, protein subunit-based vaccines, viral vector-based vaccines and virus-like particle-based vaccines. Vaccine development has five stages. In the clinical developmental stage, vaccine development can be sped up by combining phase 1 and 2. The vaccines can also be approved more swiftly on an emergent basis and released sooner for usage. The United States Food and Drug Administration (USFDA) has approved Pfizer-BioNTech, Moderna and Janssen coronavirus disease 2019 (COVID-19) vaccines for emergency use. There are other vaccines that have been approved around the world. The mRNA vaccines have been created using a novel technology and they contain a synthetically created RNA sequence of virus fragments encoding the S-protein which is injected. These vaccines have a relatively low cost of production and faster manufacturing time but can have comparatively lower immunogenicity and more than one dose of vaccine may be required. In the case of viral vector-based vaccines, genes encoding the SARS-CoV-2 S protein are isolated and following gene sequencings are introduced into the adenovirus vector. These vaccines have a relatively fast manufacturing time but the efficacy of the vaccine is variable based on the host's immune response to the viral vector. At the time of this paper, there were 81 vaccines in clinical development stage and 182 vaccines in preclinical development stage. Vaccines are an essential tool in our battle against COVID-19. Some of the COVID-19 vaccines have completed their phase III trials while many other potential vaccines are still in developmental stages. It used to take close to a decade for a vaccine to be developed and undergo rigorous testing until its production and availability to the public, but over the past year, we have seen multiple vaccines in different phases of testing against SARS-CoV-2 virus.

Purpuric Rash and Thrombocytopenia After the mRNA-1273 (Moderna) COVID-19 Vaccine.

The mRNA-1273 vaccine, popularly called the "Moderna vaccine" is being widely administered in the United States for the prevention of COVID-19 infection since December 2020. Mild to moderate intensity side effects like low-grade fever, myalgia, chills and malaise were reported in the trials related to the vaccine. With this case report, we report a case of purpuric rash and thrombocytopenia after receiving the first dose of the m-RNA-1273 vaccine. The patient, in this case, is a 60-year-old male patient who received the first vaccine dose and within two days, he developed diffuse papular rash associated with some thrombocytopenia. He had a history of tobacco use, Hepatitis C liver cirrhosis, chronic kidney disease stage 4, untreated hypertension and systolic congestive heart failure at the baseline. With review of the limited literature related to the vaccine and its side effect profile and with no other etiology explaining the sudden onset of rash, we attribute this thrombocytopenia and purpuric rash as the side effects of the mRNA-1273 vaccine.

COVID-19 Encephalopathy in Adults.

Many patients with COVID-19 are asymptomatic. However, among the patients that are symptomatic, influenza-like illnesses including fever, myalgia and respiratory symptoms seem to be the most common presentation across age groups. Though respiratory illness seems to be the primary presentation, about 36.4% to 69% of hospitalized COVID-19 patients have exhibited neurological manifestations.  We present two patients who were hospitalized for the presenting symptom of acute encephalopathy. Both the patients regained consciousness within 24 to 48 hours of initiating treatment. The first patient was known to have mild cognitive impairment and a thorough work-up was done in the emergency department which did not reveal any other causes apart from positive SARS-CoV-2 rapid PCR test. The second patient was from a long-term care facility with underlying dementia, usually alert, awake and oriented to self and presented with severe encephalopathy with a Glasgow Coma Scale of 3 on admission. Her work up was notable only for a positive SARS-CoV-2 rapid polymerase chain reaction test. Both patients responded well to standard remdesivir and steroid therapy and returned to baseline cognition. SARS-COV 2 virus appears to be a causative agent of acute onset encephalopathy. Very little is known about the pathophysiology of neurological manifestations in COVID-19 illness. There are several theoretical possibilities of pathogenesis such as of blood-brain barrier disruption secondary to SARS-CoV-2 binding to angiotensin-converting enzyme 2, autoimmune sequelae, ischemic injury via systemic hypoxia or local vascular endothelial information or thrombosis, toxic metabolic encephalopathies and long-term impact of systemic proinflammatory state that have been considered.

Pediatric Care Struggles of US Trained International Medical Graduate Pediatricians in COVID-19 Pandemic.

BACKGROUND: Pediatrician shortage and healthcare access has been a serious issue especially in medically underserved and rural areas aplenty in the USA and has further worsened during the coronavirus disease 2019 (COVID-19) pandemic. Many US trained international medical graduates (IMGs) on a visa status serve these areas to fill in the physician gap. These physicians are usually on a visa and the majority of them have approved immigration petitions. During this pandemic, the sudden changes in immigration policies in addition to the longstanding administrative backlog and processing times had posed new challenges to the pediatricians and the communities served by them. The objective of this study was to determine the demographics, level of training and practice, immigration status, the clinical role they played in the communities they served and the various professional and personal setbacks they faced during the pandemic. METHODS: A survey was created and data were collected using data collection platform "Survey Monkey". Screening questions were designed to include only IMG pediatricians on a visa status. RESULTS: A total of 267 IMG pediatricians qualified for the survey on a nationwide basis. Of the physicians that participated in the survey, 58.4% were working in either medically underserved or physician shortage areas, 36% of the total physicians were working in a rural setting, 10.6% of the pediatricians had to be quarantined due to exposure to COVID-19, 0.8% were infected with COVID-19 themselves, and 81.3% of the pediatricians had faced hindrance in being able to work at a COVID-19 hotspot due to work site restrictions because of their visa status. CONCLUSION: IMG pediatricians play a valuable role in taking care of the children in medically underserved areas. The challenges surrounding the immigration backlog are contributing to significant hardships for these pediatricians and their families and are causing a hindrance to healthcare access to the children in medically underserved communities during the pandemic especially limiting the pediatricians' scope and geographic radius of the practice, thus not allowing them to practice to the full extent of their license.

Primary Care Shortage in Medically Underserved and Health Provider Shortage Areas: Lessons from Delaware, USA.

OBJECTIVE: To examine the reasons contributing to the physician shortage in the country's medically underserved areas using the state of Delaware as a focus state. METHOD: A literature review regarding the shortage of physicians with data compilation from Delaware Department of Public Health (DPH) and Delaware Health and Social services (DHSS) was performed. A review of the "Conrad 30 J1 VISA waiver program," the most important and primary supplier of physicians to underserved areas of the state was performed. A survey interviewing the physicians recruited through this program to identify any challenges faced by them was designed and conducted. RESULTS: The number of primary care physicians providing direct patient care in Delaware in 2018 had declined about 6% from 2013. The average wait time to see a PCP was 8.2 days in 1998 as compared to 23.5 days in 2018. Forty-six percent of physicians serving in HPSAs in Delaware are IMGs recruited through the J1 VISA waiver program. Eighty percent of these IMGs are actively considering leaving the United States due to anxieties around physician immigration policies, mainly "Immigration backlog." CONCLUSION: The existing programs to recruit physicians to underserved areas seem to be inadequate. The state and the hospital systems should be able to utilize the J1 program to its full potential and focus on retaining these physicians after their assigned services. As the challenges of IMGs continue to worsen every day; the medical societies, hospitals, the state and federal government should advocate for policies that resolve these challenges.