Hot Topics in Medical Affairs – Check out the latest news in Medical Affairs in Medicines Development. IFAPP Academy provides an online, continuing professional development course, Medical Affairs in Medicines Development, resulting in the Professional Certification, Certified Medicines Development (CMD).
Conversations with the Academy series webinar, March 30, 2021
2020 pummeled us with unforeseen and unfathomed circumstances, demanding sweeping changes with traditional mindsets, policies, and perspectives, even as the COVID-19 pandemic took a grievous and burdensome toll on life, healthcare systems, and the global economy.
From the early days, philosophy has expounded on the ethics in relationships between individual virtue, society, and the State. Fast forward to 2021, over a year into the medical and socio-economic upheaval ravaged by the pandemic. We confronted science being pitched versus politics. We witnessed unparalleled collaboration between biopharmaceutical rivals. We grappled with individual rights versus societal interests. We asked ourselves what is just, what is fair, what is legal, and what is right?
Guiding us through this minefield of emerging scenarios, Arthur Caplan, Professor, Division of Medical Ethics, New York University (NYU) School of Medicine, Sandor Kerpel-Fronius, Professor, Clinical Pharmacology, Semmelweis Medical University, Budapest, and Pravin Chopra, Chair, Scientific Advisory Committee, IFAPP Academy, reflected on the contentious bioethical issues in the year that has been….
The panel deliberations focused on the several important ethical, policy, and access issues that have become pressing and thrown into the limelight, contesting traditional thinking and concepts, even as various COVID-19 vaccines are being made available in different nations.
The accelerated development of these vaccines, some deploying novel platforms, receiving Emergency Use Authorization (EUA) in the backdrop of the pandemic, has triggered bioethical concerns around informed consent in emergency settings and for unapproved products. This has also drawn attention to revisiting traditional tenets with human challenge studies, clinical trial design elements, and regulatory oversight of the drug development paradigm. Moreover, patient engagement and advocacy groups are becoming increasingly empowered with seeking information about and pre-approval access to investigational treatments and biopharmaceutical innovation.
Who ought to receive vaccines first when they are still scarce and with usage restrictions? What are the overriding scientific, ethical, and political factors influencing national guidance on the use of vaccines, even without completed phase III evaluation of efficacy and safety, when vaccine supply is inadequate? Should a single-dose or even a delayed booster injection immunization strategy be deployed for compensating limited vaccine stores? How and when do nations decide whether to share vaccines with other nations? What is the optimal balance in the global dilemma of pursuing worldwide control of the pandemic by sharing vaccine rations with low-to-middle income countries internationally vis-à-vis prioritizing more complete vaccine coverage locally in wealthy nations? When, if ever, should vaccines be mandated, by whom, for whom, with what documentation — and with what penalties for non-compliance?
The benefits of vaccination are real and proven. Still, even with their perceived potential for effecting control of COVID-19 spread and damage, there remain multifarious difficult questions that must yet be addressed by individuals, society, and governments.
The engaging session elaborated on the multitude of bioethical considerations and issues arising with the COVID-19 vaccine development experience, the place of human challenge studies in assessing new vaccine candidates, and the impediments with patient informed consent vis-à-vis placebo-controlled trials under EUA settings. An audience poll on the value and legitimacy of challenge trials with COVID-19 vaccines provoked a dichotomous split reaction – reinforcing the contentious nature of either stance! The discussions generated awareness of regulatory learnings for future approvals of new drugs for very sick patients, and the likely longer-term implications for future medicines development processes and clinical trial design considerations
More critically, the discussants shared perspectives on the escalating debate surrounding vaccine policies and guidance with prioritization and allocations both within and between countries and the inevitable confrontations around equitable global vaccine access and administration logistical challenges, especially in emerging economies.
In parallel with the emphasis on strategies for addressing vaccine hesitancy and countering disinformation, a major patient advocacy and privacy issue that will necessitate urgent and thoughtful resolution hinges around vaccine mandates and immunity passports – especially with regard to data standardization and sharing across national borders, with increasing population mobility and interdependence of global economies. Notably, would be the moral and ethical connotations of excluding and depriving the social liberties of the large population groups not yet having access to vaccines?
Not unexpectedly, several of the themes addressed on this platform are already hitting the media waves globally! If you missed this fascinating discourse, a recording is offered here.
These are hard conversations around a somber reality that we must have – as the very essence and ethos of our society depends on it. Yet, there is hope that science, ethics, and above all, humanity shall prevail.
Conversations with the Academy series webinar, February 26, 2021
Tackling the plethora of emerging situations, Otfried Kistner, Independent Vaccine Expert and Consultant, Soneil Guptha, Pharmaceutical Physician-Scientist, and Kamlesh Thakker, Clinical Pharmacologist and Independent Consultant, delineated the urgent need for safe and effective vaccines, which, if deployed with timely distribution and extensive populations coverage, could potentially contribute to generating herd immunity and effective control of COVID-19, having afflicted tens of millions of people in a worldwide pandemic.
The panel warned that SARS-CoV-2 is a novel viral strain that is spreading rampantly and globally – even with evolving mutant strains — and consequently, traditional processes and timelines for vaccine development would fail to provide an immediate and comprehensive solution. In a pandemic situation, urgent clinical development and widespread rollout of new vaccines become paramount. While emphasizing adherence to the principles of relevance and limitations of immune response markers and systematic approaches to assessing safety and reactogenicity, a re-thinking around the efficient design of efficacy and safety studies, with clinically relevant case definitions, is warranted. More importantly, this knowledge needs to be continually supplemented and updated with real-world monitoring and evaluation of disease understanding and the comparative effectiveness of vaccines across diverse patient demographics and against new mutant forms.
To address this pressing challenge globally, several vaccines developed in such an accelerated manner have been authorized by nations across the world for emergency use in the pandemic and for large-scale deployment against the spread of COVID-19 and the rapid achievement of herd immunity. While some of these have even utilized novel mRNA platforms, it is critical to continually underscore that fundamental clinical development principles are not compromised. The panel cautioned that the utility of both traditional and newer approaches needs to be assessed in the context of transparent data and peer-reviewed results for the various Emergency Use Authorization (EUA) products.
Moreover, as has been the concerning experience with earlier vaccines, it is imperative to dispel COVID-19 vaccine hesitancy, even while advocating for equitable vaccine access across the world’s nations, if the desired herd immunity is to be successfully achieved. Judicious communication and intervention strategies to educate an often-circumspect public and dispel disinformation contributing to such vaccine hesitancy will need to be proactively considered and implemented, alongside fairness with access and vaccination outreach.
Additionally, the global audience was apprised on the spectrum across fundamentals and translational science considerations in vaccine development targeting SARS-CoV-2, encompassing accelerated clinical development of COVID-19 vaccines and the evolving regulatory considerations and guidance for their EUA and disbursement. Perspectives on the fast-tracked clinical assessment and development of COVID-19 vaccines during this pandemic were also shared. What could have been done differently to benefit and/or improve the outcomes and assessments? What elements could gainfully be extrapolated to overall medicines development? The potential implications of this paradigm shift on future drug development processes and access to innovative medicines, especially in critical care and rare diseases, are already the subject of intense public interest and scrutiny.
The panel also explored the typical profile of the vaccine refuser – stemming from a distrust of governments and staunch religious and political beliefs, among other personal experiential factors – and stressed the value and importance of medically factual disease and vaccine education in countering vaccine hesitancy and combating disinformation, while seeking to optimize access and vaccination rates amongst the world’s diverse populations.
We stand today at the crossroads of a global challenge without precedent that demands researchers, policymakers, and governments address multiple dimensions which go far beyond the ramifications of the COVID-19 pandemic. And, while vaccines have transformed public health, particularly since national programs for immunization first became properly established and coordinated in the1960s, their traditional development typically requires years of research and efficacy and safety testing before reaching the clinic. But, 2020 saw a seismic shift in drug development paradigms as scientists embarked on a race to produce safe and effective coronavirus vaccines in record time.
What have we gleaned along this journey, when and where do we seek answers for the myriad of emerging ethical dilemmas? How do we leverage leanings for improving public health measures and outcomes? What are the implications for future drug development processes?
The Conversations with the Academy platform, under the aegis of the IFAPP Academy’s Value-Added Program offerings, explores this burgeoning medical, socio-economic, and ethical conundrum.
Our sincere appreciation for the perceptive opinions from our expert faculty and hosts. And, we remain encouraged by your continued patronage of the IFAPP Academy’s initiatives.
Click the below links to learn more about these webinars:
Last March 3rd, IFAPP Academy has co-organized jointly with Medical Affairs. Professional Society. (MAPS) and Australian Pharmaceutical medical and scientific Professionals Association (APPA), a dedicated webinar related to Professional Education, Capabilities, and Identity in Medical Affairs.
This virtual meeting of the medical affairs community investigated currently available educational opportunities with the view of developing a universally recognized base qualification that can be regionally adapted for medical affairs and medicines development professionals.
The main topics discussed were: Medicines Development Professional Identity; Core Competencies in Medical Affairs; Professional Education in Medical Affairs – the IFAPP Academy / King’s College experience; personal experience from University of New South Wales (UNSW) Alumni, and the experience of the University of Sydney with a Master of Medicine (Pharmaceutical and Medical Device Development) course.
The following quotes and summaries were retrieved from the panelists’ presentations:
Victoria Elegant, Amgen’s Vice President and Region Head of MAPS JAPAC, commented that the job requirements had changed substantially. “We’ve gone from needing to know about our therapeutic areas to actually needing to know about therapeutic areas plus needing to know about safety, about drug development, about regulatory, about access, and that’s why these courses are so critically important,” she said.
Matthew Britland, Vice President, APPA, explained to the audience: “We all know that medical affairs has exponentially grown over the last decade. It’s moved from very much a support function to a trusted strategic partner – and the skills set has also evolved significantly over the past few years. But there’s still a void in a globally recognized advanced scientific qualification or a capability framework across medical affairs, and there’s certainly no accreditation or certification that’s accepted across industry and peak bodies.”
Gustavo Kesselring, IFAPP Academy Vice President, stated: “At IFAPP Academy, our strong belief is that education and training for key professional development is the cornerstone for everything that we do in our professional life. Unfortunately, when we graduate as physicians or pharmacists or nurses, or in other areas of health science, we do not learn the science that is behind medicines development. We know the foundational knowledge of this science is unique and needed for the progression of our careers.”
“Our credo is we need a professional identity with a strong career pathway that needs to be developed (either as) medicines development or medical affairs professionals.”
Peter Stonier, Visiting Professor in Pharmaceutical Medicine, King´s College London, gave a detailed explanation about the IFAPP-King´s College London Professional Certification Program of Medical Affairs in Medicines, and its success in delivering an online competency knowledge-based course in the last 5 years to more than 400 students from 55 countries.
At the end, Lara Stallard-Taylor, Roche’s Senior Medical Manager, who completed a Masters of Pharmaceutical Medicines from UNSW, said ensuring consistent industry knowledge through education is the key. “We all find our way into medical affairs via our own path. It´s really important to have a rich pool of experience and diversity, but a foundation course like a Masters of Pharmaceutical Medicine for both aspiring and existing medical affairs professionals would provide a consistent industry knowledge base”.
Since joining the International Council for Harmonization (ICH) as a full regulatory member in June 2017, China has made great efforts to improve various laws, regulations, and guidelines.
The Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) usually issues multiple guidelines before the weekends and each holiday. We call these a big “holiday tribute” for patients, policy-makers, and the pharmaceutical industry. Since January 1st, 2021, 23 guidelines have been issued by CDE, nine of which came before the Spring Festival, including:
Guidelines for Clinical Trials of Antimicrobial Drugs for Complex Abdominal Infections (No. 10 of 2021) [1];
Standardizes the clinical research and evaluation of antibacterial drugs for complicated intra-abdominal infections. Gives recommendations under the framework of Guidelines for Clinical Trials of Antibiotics (Apr.3, 2015) [2].
Guidelines for the Research on Generic Drugs of Fulvestrant Injection (try-out) (No. 11 of 2021);
Alleviates the shortage of clinical supply of fulvestrant injection and accelerates the marketing of its generic drugs. Provides guidance on the technical requirements for pharmaceutical research and non-clinical research during the development of generic drugs, and clarifies the eligibility criteria for a waiver of bioequivalence studies in humans [3].
Guidelines for Clinical Trials of Intravenous Human Immunoglobulin for the Treatment of Primary Immune Thrombocytopenia (try-out) (No. 12 of 2021);
Guides and standardizes the clinical trials of immunoglobulin for intravenous administration (IVIg) for the treatment of primary immune thrombocytopenia (ITP). It mainly describes the key content in pre-marketing and post-marketing clinical trials of IVIg for ITP patients; outlines the required trials for post-approval changes (e.g., chemistry structure and activity). In the end, it gives advice on the risk management plan [4].
Guidelines for the Design of Clinical Trials of Oncolytic Viruses (try-out) (No. 13 of 2021);
Guides and standardize the clinical trials of oncolytic viruses for the treatment of malignant tumors. It describes key points in the design of exploratory and confirmatory clinical trials. What’s more, it gives advice on the risk management plan [5].
Guidelines for Clinical Trials of Immune Cell Therapy Products (try-out) (No. 14 of 2021) [6];
Specifies the clinical recommendations for immune cell therapy products in clinical trials under the framework of Guidelines for Research and Evaluation of Cell Therapy Products (December 22nd, 2017) [7]. Provides guidance on the clinical design for exploratory and confirmatory trials of Immune Cell Therapy Products. What’s more, it outlines the suggestions on long-term follow-up and post-marketing study or surveillance.
Guidelines for Post-approval Clinical Changes to Chemical Drugs and Biological Products (No. 16 of 2021);
Clarifies the clinical changes of an approved drug in China and applies to chemicals, preventive biological products, and therapeutic biological products [9].
Guidelines for Non-clinical Research and Evaluation of Gene Therapy Products (Draft, opening for Comments).
Provides recommendations for the non-clinical development of gene therapy products. It advises that non-clinical studies should follow the 3R principle of “Replacement, Reduction, Refinement, to avoid unnecessary use of animals and other resources [11].
India’s regulatory authority granted a restricted emergency approval to two COVID-19 vaccines in India on January 3rd, 2021. The first of these was a recombinant chimpanzee adenovirus vector vaccine (ChAdOx1 nCoV-19). The second approved vaccine was an indigenously developed whole virion inactivated coronavirus vaccine (BBV152).
Oxford/AZ- ChAdOx1 nCoV-19, marketed as COVISHIELD, has been manufactured by Serum Institute of India (SII) under the expert foundation laid by Oxford University and Astra Zeneca. Even before its emergency approval, more than 40 million doses of the vaccine had already been manufactured by the SII under the at-risk manufacturing and stockpiling license from the DCGI. A pooled analysis of phase 2/3 trials conducted in over 20,000 participants from the UK, Brazil, and South Africa showed that the ChAdOx1 nCoV-19 vaccine had an acceptable safety and immunogenicity profile with efficacy against symptomatic COVID-19. To establish the safety, efficacy, and immunogenicity of COVISHIELD in India, SII together with the Indian Council of Medical Research (ICMR) came forth to conduct a phase II/III clinical trial at 15 different centers across India. Interim safety and immunogenicity data obtained from this trial were comparable to the data from an overseas clinical trial conducted with COVISHIELD. Considering the above data, the Subject Expert Committee of Central Drugs Standard Control Organization (CDSCO), India after due consideration and detailed contemplation, recommended that COVISHIELD be granted permission for restricted use in emergency situations subject to certain regulatory conditions. The final results of the trial are still awaited.
BBV152 (COVAXIN) has been developed indigenously by an Indian pharmaceutical company: Bharat Biotech. There is sufficient safety and immunogenicity data from pre-clinical studies. The phase I data recently published in the Lancet portrays that COVAXIN was seen to enhance immune responses and had acceptable safety outcomes. Phase II trial has also been completed, and phase III trial is ongoing in about 25,800 Indian volunteers. In India, the regulatory authority granted an emergency authorization to COVAXIN based on pre-clinical data, Phase I, Phase II data, and interim results generated from the phase III clinical trial.
The approval of COVID-19 vaccines in India is a very important milestone that will lay the foundation for India to supply the vaccines to many other countries in the world. World Health Organization has welcomed and encouraged the regulatory decision on the emergency use authorization of COVID-19 vaccines in India. Although a vast number of people in India have applauded the emergency authorization of COVID-19 vaccines, there are a good number of people who have been shadowed by a sense of doubt fueled by the lack of transparency about the clinical trial protocols and also in part by the non-availability of the detailed trial results in the public domain. In addition to this, Phase III trials in India with both the vaccines have not been completed yet. Even though the complete phase III trial results are not yet available, it is important to educate the public that sufficient data has been generated from the earlier phases of clinical trials and interim results of the phase III trial. This highlights the importance of educating recipients about the regulatory protocols and the essentiality of vaccination in health emergency situations, as posed by the pandemic. Keeping this in mind, the Ministry of Health and Family Welfare in India has created a web portal and helpline number to solve queries related to COVID-19 vaccination.
The COVID-19 vaccination drive in India began on January 16th, 2021, with the initial beneficiaries consisting of Healthcare workers. The drive has now been extended to frontline workers. To date, about 7 million people have already been inoculated with the first dose of the vaccine against COVID-19. India has emerged to be the fastest country to vaccinate a vast number of people within a short time. However, it seems like the journey has just begun. The challenge still seems far from completion considering the huge population of India, i.e., 1.38 billion.
Mohapatra PR, Mishra B. Regulatory approval of COVID-19 vaccine for restricted use in clinical trial mode. Lancet Infect Dis. 2021 Jan 25:S1473-3099(21)00045-1.
Voysey M, Clemens SAC, Madhi SA, et al; Oxford COVID Vaccine Trial Group. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 January 9th;397(10269):99-111.
Ella R, Vadrevu KM, Jogdand H, et al, Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis. 2021 Jan 21:S1473-3099(20)30942-7.
Nishtha Khatri, MD
Assistant Professor, Seth GS Medical College and KEM Hospital, India
Disclaimers
The material in these reviews is from various public open access sources, meant for educational and informational purposes only
Any personal opinions expressed are those of only the author(s) and are not intended to represent the position of any organization(s)
No official support by any organization(s) has been provided or should be inferred
Conversations with the Academy Series continues to garner promising participation by the global learning community
The December event in the series featured an eminent panel exploring evolving Health Economics Outcomes Research (HEOR) concepts, driven by the changing healthcare landscape and increasing expectations to demonstrate value. Dr. Laurent Pacheco, Managing Director, Syneos Health Consulting; Dr. Seema Haider, International HEOR Advisor; and Dr. Jennifer Stephens, Partner, and Clinical Director, Pharmerit, addressed the challenges and trends in the healthcare market across the globe, with the HEOR audience expanding beyond payers and Health Technology Assessment (HTA) bodies, to a variety of stakeholders, including patients and regulators.
Physicians need HEOR data to inform their treatment decisions to meet the healthcare needs of patients best. Importantly, HEOR brings a real-world perspective. As countries adopt universal healthcare systems and develop HTA frameworks, they need transparent, understandable, and effectively communicated HEOR data to help inform healthcare decision making.
The panel highlighted perspectives to better deliver and communicate HEOR information and real-world data. They emphasize cross-functional collaboration in biopharmaceuticals, patient centricity, and leveraging digital transformation. If you missed this, a recorded session is offered at https://youtu.be/kYmr7IrDtk8
The most recent discussion, Real World Evidence and Real-World Data: from Disease Management to Evaluating Drug Safety and Effectiveness, on January 28th, seeks to analyze the rapidly increasing interest and relevance of real-world evidence to answer clinical, regulatory, and policy-pertinent questions, which cannot be wholly or directly addressed by traditional randomized controlled trials. The recording will be made available soon on IFAPP Academy’s YouTube page.
As always, we express our sincere appreciation for the keen insights from our expert faculty and hosts. Furthermore, we are motivated by your active participation at these events.
Under the umbrella of the IFAPP Academy’s Value Added Programs and Services, offering continuing professional development initiatives and avenues for networking for our expanding learning community, the Conversations with the Academy webinar programs have garnered enthusiastic engagement.
In the third event in the series Dr. Mark Lightowler, CEO, Phorix Limited, highlighted The Role of Digital Tools in Changing Health Behavior, exploring the evidence for behavioral change parameters – e.g., physical activity, medication adherence, smoking cessation — to be considered in health outcome programs, in tandem with patient engagement tools. While evaluating how innovative digital tools are unlocking our understanding of behavior and our ability to change, Dr. Lightowler shared insights and resources to promote behavioral change in the workplace.
Following on, Dr. Birka Lehmann, Senior Expert Drug Regulatory Affairs, reviewed theNew European Regulation for Clinical Trials, stressing the need for further legislative changes to drive a more harmonized approach by regulatory agencies granting clinical trials and Ethics Committees agreements. Dr. Lehmann outlined the transition with the regulations, which underscore the harmonization of conditions, emphasizing the new challenging interactions needed by regulatory agencies, Ethics Committees, and applicants. New timelines have to be respected by all involved partners. That e-handling of applications and approvals is imperative. Don’t miss the recording.
We express our sincere appreciation for the invaluable inputs and contributions from our expert faculty and hosts. We are encouraged by your active participation at these events and look forward to your continued support and engagement.
Yesterday, Pfizer and BioNTech announced that the first participants were dosed in the U.S. as part of the Global COVID-19 mRNA Vaccine Development Program
On May 5th, 2020 at 6:45 AM EDT, NEW YORK & MAINZ, Germany–(BUSINESS WIRE)–Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that the first participants have been dosed in the U.S. in the Phase 1/2 clinical trial for the BNT162 vaccine program to prevent COVID-19. The trial is part of a global development program, and the dosing of the first cohort in Germany was completed last week.
The Phase 1/2 study is designed to determine the safety, immunogenicity and optimal dose level of four mRNA vaccine candidates evaluated in a single, continuous study. The dose level escalation portion (Stage 1) of the Phase 1/2 trial in the U.S. will enroll up to 360 healthy subjects into two age cohorts (18-55 and 65-85 years of age). The first subjects immunized in Stage 1 of the study will be healthy adults 18-55 years of age. Older adults will only be immunized with a given dose level of a vaccine candidate once testing of that candidate and dose level in younger adults has provided initial evidence of safety and immunogenicity. Sites currently dosing participants include NYU Grossman School of Medicine and the University of Maryland School of Medicine, with the University of Rochester Medical Center/Rochester Regional Health and Cincinnati Children’s Hospital Medical Center to begin enrollment shortly.
“With our unique and robust clinical study program underway, starting in Europe and now the U.S., we look forward to advancing quickly and collaboratively with our partners at BioNTech and regulatory authorities to bring a safe and efficacious vaccine to the patients who need it most. The short, less than four-month timeframe in which we’ve been able to move from pre-clinical studies to human testing is extraordinary and further demonstrates our commitment to dedicating our best-in-class resources, from the lab to manufacturing and beyond, in the battle against COVID-19,”
Albert Bourla, Chairman and CEO, Pfizer
Pfizer and BioNTech’s development program includes four vaccine candidates, each representing a different combination of mRNA format and target antigen. The novel design of the trial allows for the evaluation of the various mRNA candidates simultaneously in order to identify the safest and potentially most efficacious candidate in a greater number of volunteers, in a manner that will facilitate the sharing of data with regulatory authorities in real-time.
“It is encouraging that we have been able to leverage more than a decade of experience in developing our mRNA platforms to initiate a global clinical trial in multiple regions for our vaccine program in such a short period. We are optimistic that advancing multiple vaccine candidates into human trials will allow us to identify the safest, most effective vaccination options against COVID-19,”
CEO and Co-founder of BioNTech, Ugur Sahin.
During the clinical development stage, BioNTech will provide clinical supply of the vaccine from its GMP-certified mRNA manufacturing facilities in Europe.
In anticipation of a successful clinical development program, Pfizer and BioNTech are working to scale up production for global supply. Pfizer plans to activate its extensive manufacturing network and invest at risk in an effort to produce an approved COVID-19 vaccine as quickly as possible for those most in need around the world. The breadth of this program should allow production of millions of vaccine doses in 2020, increasing to hundreds of millions in 2021. Pfizer-owned sites in three U.S. states (Massachusetts, Michigan and Missouri) and Puurs, Belgium have been identified as manufacturing centers for COVID-19 vaccine production, with more sites to be selected. Through its existing mRNA production sites in Mainz and Idar-Oberstein, Germany, BioNTech plans to ramp up its production capacity to provide further capacities for a global supply of the potential vaccine.
BioNTech and Pfizer will work jointly to commercialize the vaccine worldwide upon regulatory approval (excluding China, where BioNTech has a collaboration with Fosun Pharma for BNT162 for both clinical development and commercialization).
This article has been prepared by Dr. Penny Ward FFPM, with input from Professor Tim Higenbottam PFPM, Dr. Flic Gabbay FFPM, Dr. Bob Holland FFPM, Dr. Sue Tansey FFPM, and Dr. Tahir Saleem MFPM.
It is provided for information and does not constitute advice or represent official FPM views or policy.
Summary
This review addresses current knowledge concerning SARS-CoV-2 and COVID-19 disease including:
Epidemiology of the outbreak
SARS-CoV-2 viral life cycle and clinical features of COVID-19 Disease
Current Treatment
An enormous effort is ongoing across the life science industry in the UK and beyond to address this pandemic. It is hoped that the insights provided in this article will excite interest and support for the challenge. Future articles will address work ongoing to develop a vaccine and effective antivirals for treatment/prophylaxis.
Introduction
At the end of the Great War, a conflict which convulsed most countries in the world over four years and killed an estimated 40 million soldiers and civilians among participating nations, the world was seized by a pandemic of Influenza, which, in the space of a year, spread to every country on earth, infected almost 500 million and killed 100 million people. Three months into the 101st anniversary year of that great pandemic, we are again witnessing a rapidly spreading, highly infectious serious acute respiratory syndrome (SARS) sweep across the world. Since first recognition in Wuhan, China in December 2019 to the time of this review, Corona Virus Disease -19 (COVID-19), caused by infection with a novel coronavirus, SARS-CoV-2, has spread to virtually all countries, infected over 900,000 individuals and caused more than 40,000 deaths. It is still increasing rapidly1. This bulletin reviews the state of understanding of the virus, the pattern of disease in infected individuals and discusses advances made and work ongoing to facilitate efficient diagnosis, prevention, and treatment of this significant health threat.
The Coronaviridae
Coronavirus disease was first recognized in humans in the 1930s, with the first virus (HCoV-229E) isolated in 19652. Subsequently, three further CoVs were identified in humans (HCoV-NL63, HCoVOC43, and HCoV-HKU1). These viruses are endemic in humans and, after rhinoviruses, are an important cause of the common cold, with outbreaks occurring throughout the year, but more frequently in winter and spring in temperate climates. While adults generally experience mild cold symptoms, among individuals with asthma/COPD exacerbations may occur. Infection may be more severe in infants and young children, causing tracheolaryngobronchitis (croup), bronchitis and pneumonia3. In November 2002 an outbreak of serious acute respiratory syndrome (SARS) was found to be due to a fourth, highly pathogenic, coronavirus the SARS coronavirus. The disease originated in China and subsequently spread to Vietnam, Hong Kong, Taiwan, Singapore, and Canada. Between its first and last appearance, 8096 cases were reported to the World Health Organisation (WHO) with 711 deaths, giving a case fatality rate (CFR) of 9.6%. In affected countries, outbreaks were contained by vigorous identification of cases and enforced quarantining of contacts3. In Taiwan, where an outbreak followed the return of an infected traveler returning from Guandong, China, 671 cases were identified and 131,132 people were quarantined4. The last case from this episode was reported in July 2003, although three small laboratory associated outbreaks have occurred since then involving 11 patients. The causative virus, the betacoronavirus, SARS CoV, has not been circulating in humans since. A fifth coronavirus was identified in 2012 in the UK following hospital admission of a patient with a SARS-like illness. Middle East Respiratory Syndrome (MERS) CoV has resulted in a limited number of outbreaks, mostly in Saudi Arabia and other middle eastern countries. Human to human transmission of this disease has, to date, been limited to close contacts of affected cases in households or healthcare settings. The CFR in this disease exceeds 30% 3.
Figure 1: Structure of Human Coronavirus (from Korsman S, Virology 2012 Pub Churchill Livingtone)
Virus Structure and Replication:
Human coronavirus particles are generally spherical, 120-160nm diameter and typically decorated with large (~20 nm), club- or petal-shaped surface projections (the “peplomers” or “spikes”), which give an image resembling the solar corona on electron micrographs of infected tissues and hence to the family name (Figure 1).3
Receptor Binding
Coronaviruses have a large single positive RNA stranded genome of 28-32 kilobase size (making it the largest RNA genome of the RNA virus family) enclosed in a nucleocapsid of helical symmetry (Figure 2). These viruses infect human cells via S (spike) protein binding to receptors on host cells, followed by the release of viral RNA into the cell cytoplasm. Various host receptors have been associated with the different human coronaviruses so far described: the host receptor for HCoV-229E is aminopeptidase N while HCoV-OC43 uses 2,3 or 2,6 alpha sialic acid receptors (as does influenza virus). The S protein of SARS CoV binds to angiotensin-converting enzyme 2 (ACE2) and of MERS CoV to dipeptidyl peptidase 4 (DPP4)5. SARS-CoV-2 has also been demonstrated to bind to ACE2, a transmembrane receptor that is widely expressed in lung, heart, kidney and gastrointestinal tissue6.
Intracellular replication
Following receptor binding, the virus must then access the cell cytoplasm. This is assisted by acid-dependent proteolytic cleavage of S protein by a cathepsin, TMPRRS2 or another protease, followed by fusion of the viral and cellular membranes. S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage important for separating the receptor-binding domain (RBD) and fusion domains of the S protein and the second for exposing the fusion peptide (cleavage at S2′). Fusion generally occurs within acidified endosomes, but some coronaviruses can fuse at the plasma membrane. Following this, the viral replicase gene, which consists of two open reading frames (ORFs) coding for two polyproteins pp1a and pp1ab. These polyproteins contain all the non-structural proteins (nsps) of the virus which are essential for intracellular replication. The polyproteins are cleaved to form individual nsps by proteases, including one or two papain-like proteases (PLpro) (depending on the coronavirus sp) and a serine-type protease, the Main (M)protease. Many of these nsps then assemble into the replicase-transcriptase complex (RTC) which replicates the viral RNA. Following replication and viral RNA synthesis, the viral structural proteins, S, E, and M are translated and inserted into the endoplasmic reticulum (ER). These proteins move into the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) where viral genomes encapsidated by N protein bud into membranes of the ERGIC containing viral structural proteins, forming mature virions.
Progeny virion assembly and budding
The M protein directs most protein-protein interactions required for assembly of coronaviruses but is not enough, alone, for virion formation. When M protein is expressed along with E protein, virus-like particles (VLPs) are formed, suggesting these two proteins function together to produce coronavirus envelopes. N protein enhances VLP formation, suggesting that the fusion of encapsidated genomes into the ERGIC enhances particle envelopment. The S protein is incorporated into virions at this step but is not required for assembly. The ability of the S protein to traffic to the ERGIC and interact with the M protein is critical for its incorporation into virions. Following assembly, progeny virions are transported to the cell surface in vesicles to be released by exocytosis (Figure 2).
Figure 2: Replication cycle of SARS-CoV-2 [1] Spike protein on the virion binds to ACE2, a cell-surface protein. TMPRSS2, an enzyme, helps the virion enter [2] The virion releases its RNA [3] Some RNA is translated into proteins by the cell’s machinery [4] Some of these proteins form a replication complex to make more RNA [5] Proteins and RNA are assembled into a new virion in the Golgi and [6] released. Sources: Song et al., ‘Viruses’, 2019; Jiang et al., ‘Emerging Microbes and Infections, 2012; ‘The Economist’.
In some coronaviruses, S protein that does not get assembled into virions transits to the cell surface where it mediates cell-cell fusion between infected and adjacent, uninfected cells. This leads to the formation of giant, multinucleated cells, which permit the virus to spread within an infected organism without being detected or neutralized by virus-specific antibodies7.
Route of Infection
The human coronaviruses may be spread via aerosol infection of the respiratory tract following inhalation of aerosol particles in the air. Large particle sizes contaminate the upper airways, but particles of <5 microns size can move into the lower respiratory tract. Coughing, spitting, sneezing and talking generate aerosols made up of mucus droplets containing the virus. In a study investigating cough aerosols, the Edmonton group demonstrated that cough aerosols are composed of droplets ranging from 0.1 to 900 microns size, of which 97 percent were less than 1 micron in size, and 99 percent less than 10 microns. While larger particles will tend to settle quickly on nearby surfaces, particles less than 2.5 microns size remain airborne for a longer time. Thus, most of the infectious particles produced by coughing will remain airborne and can be inhaled into the lungs8. Coronaviruses are relatively stable on a variety of surfaces and thus can also spread via fomite transfection by hand contact with virus particles on surfaces contaminated by respiratory secretions and subsequent touching the mucous membranes of the face (eyes, mouth, nose). Human coronaviruses can be detected in feces, and transmission via the fecal-oral route is also possible9.
Given these potential routes of infection, masking patients to provide a barrier to the coughing of aerosols into the surrounding air, isolation of cases away from others, strict personal hygiene with frequent hand washing, regular cleaning of potentially contaminated surfaces and protection against aerosol inhalation by attendants by use of respiratory protection equipment are all imperative to prevent transmission.
Pattern of Illness post infection
Asymptomatic Infection:
The proportion of infected individuals that do not develop symptoms is unknown, as the extent of population screening has been limited. Nishiura et al investigated infection rates among a group of 565 Japanese citizens returning from China in February 2020. Of the 565 returning subjects, 14(2.4%) had a positive PCR test for SARS-CoV-2 of which 5 (41.6%: 95% confidence interval (CI): 16.7%, 66.7%) were asymptomatic at the time of testing11. Mizumoto and colleagues investigated an outbreak of SARS-CoV-2 aboard a cruise ship, the Diamond Princess. A total of 634/3063 (20.7%) subjects tested were PCR positive for SARS-CoV-2 infection. Of these 320 (50.5%) were asymptomatic at the time of testing. As testing was conducted over a 14 day period and initially focused on symptomatic cases, the authors modeled these data to reflect variability in the latent period, which results in a lower estimate for the proportion of infections that remain asymptomatic – in this case 17.9% (95%CrI: 15.5–20.2%)12. Transmission of infection from asymptomatic carriers has been documented: ergo the lack of understanding of the proportion of infections that remain asymptomatic is urgently needed, both to better understand the impact of control measures as well as to correctly ascertain the risk of death following infection14. The broader testing strategy pursued in Germany is thought to be one reason for the low apparent case fatality rate (~0.7%) there compared to other EU countries such as the UK (5.2%), Italy (10.6%) and Spain (7.6%), where testing is restricted to hospitalized patients.
Symptomatic illness is associated with fever and persistent cough with some subjects complaining of fatigue, sore throat, headache, and diarrhea. Individuals may become rapidly short of breath with increasing difficulty breathing associated with declining blood oxygenation.
Reports from China and elsewhere suggest that males may be affected more severely than females, however, most patients (80%) have relatively mild, influenza-like symptoms and make a complete recovery within 10 days13.
A small proportion of predominantly older patients and those with pre-existing chronic diseases experience progressively more severe symptoms, with CT evidence of pneumonia and biochemical evidence of an exaggerated immune response potentially driven by multiple cytokines, IL-6, IL-8, IL-10, Interferon γ, and TNF-alpha which is often called a “cytokine storm”14,15. Activation of complement C3a and C5a may initiate cytokine storm and can cause thrombotic microangiopathy. It is known to be involved in many different causes of acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) following viral infections16.
Based on limited evidence, children are in the minority among the hospitalized cases in China, accounting for less than 1% of affected cases13,17. Zheng et al reported a small case series of 25 children affected by COVID-19 in China18. The median age of the children was 3 years, with the most severely affected subjects being mostly in this younger age group. Presenting symptoms included fever [13 (52%)], followed by dry cough [11 (44%)], diarrhea [3 (12%)], nasal congestion [2 (8%)], dyspnea [2 (8%)], abdominal pain [2 (8%)] and vomiting [2 (8%)]. Clinical diagnoses in affected cases were upper respiratory infection in 8 cases, mild pneumonia in 15 cases and critical pneumonia in 2 cases. Both critical cases had congenital heart disease and one required renal dialysis. Among the children with pneumonia, the majority of those in the younger age range had bilateral pulmonary involvement on CT. The two critical cases were thought to have evidence of secondary bacterial infections contributing to their illness. None of the patients in this case series died. Dong and colleagues recently described the epidemiology of COVID-19 in 2143 children, including both confirmed and suspected cases, in China19. Children under the age of 5 accounted for 1/3 of the cases, and disease in this age group, particularly in infants <1, was more likely to be severe and critical than in older children. The proportion of severe and critical cases was 10.6 %, 7.3%, 4.2%, 4.1% and 3.0% for the age group of <1, 1-5, 6-10, 11-15 and ≥16 years, respectively.
Pregnant Women:
A small case series describing the outcome of pneumonia among 15 pregnant women in China suggested that disease was relatively mild and uncomplicated in these subjects, with normal delivery and perinatal outcomes reported20. Schwartz has summarised information from this and an additional case series from China21. Maternal-fetal transmission of viral diseases is mostly (except for herpes simplex) via the hematogenous route, in which the virus circulating in the maternal bloodstream enters the placenta, reaches the chorionic villous tree and fetal blood vessels, and is transmitted to the fetus. This mechanism of transmission has been shown not to occur with infection of pregnant women SARS-CoV and MERS-CoV, although the clinical infections caused by these coronaviruses have resulted in severe maternal pneumonia, maternal deaths, and early pregnancy losses. In the cumulated experience from published reports of 38 pregnant women with COVID-19, of whom 37 had rt-PCR-confirmed SARS-CoV-2 infection, there were no cases of either severe pneumonia or maternal deaths. Although some subjects had additional co-morbid conditions, some of which were obstetric, these did not result in life-threatening maternal SARS-CoV 2 disease.
Transmissibility
The transmissibility of infection and illness is a critical component of epidemic projections and health service planning. Transmissibility is usually described by the calculation of the reproductive number R0, representing the average number of new infections generated by an infectious person in a totally naïve population. The complete calculation of this is hampered by our non-understanding of the portion of infections which remain asymptomatic. However, based on the incidence of transmission from identified symptomatic cases to contacts, R0 for SARS-CoV-2 ranges from 1.4 to 322. This is higher than the estimated R0 for the 1918 pandemic influenza23. Thus, this epidemic, which appears to be highly transmissible, is likely to have a very significant impact on the health of populations worldwide.
One of the most impressive elements of the response of the global healthcare community to the COVID-19 outbreak has been the extremely rapid development and deployment of highly sensitive and specific tests to detect the SARS-Cov-2 virus. The first patient appears to have been hospitalized in Wuhan on 12th December and by the 2nd February, a comprehensive description of the genome of the virus was published24. Reverse transcriptase-polymerase chain reaction (RT PCR) reagents have been developed to detect the virus and distinguish it from other related coronaviruses and other common viral causes of cough and fever. While robust and well-established RT-PCR technology has allowed clinical laboratories with PCR machines to develop testing capability, the methodology is relatively low throughput and has been delivered through centralized services and validated molecular pathology laboratories. Samples need to be collected (throat and nasal swabs), couriered to the laboratory, tested, the results reviewed and provided to the patient/practitioner ordering the test. Although the test itself takes only a few hours, results can take several days to be delivered. The deployment of RT-PCR tests has been rather variable internationally, both in terms of the numbers of operational laboratories and in terms of the availability of testing kits. In the UK currently, capacity is limited and hovering at around 5000-8000 subjects tested per day as of 010420, although attempts are being made to increase this to a rate of 25000 per day. The life sciences community is working to develop variants of the RT PCR test with higher throughput and with faster turnaround times; examples include droplet digital PCR, and of particular interest to clinicians, near-patient automated PCR devices. As of 24th March, more than fifty commercially available tests (nearly all PCR based) were available across the globe claiming some sort of regulatory approval (CE-mark, FDA-EAU, CLIA lab) including several near-patient devices and kits.
RT-PCR tests are extremely sensitive and specific and therefore provide a “gold standard” for diagnosis of COVID-19 by the detection of SARS-Cov-2 genomic material. However, limitations of this method are that while it confirms the presence of viral RNA, it does not provide information on the continued presence of infectivity. This is an important consideration given the occasional report of a positive PCR test following previous negative assays in recovering patients. In addition, a PCR test does not detect prior infection or immunity to future infection.
Rapid Diagnostic Tests:
Other approaches are now in rapid development. Alternative means to detect the virus include the detection of viral proteins (immunoassays and analogous methods) and non-PCR based detection of the viral genome. None of these tests are currently available clinically but they do eventually offer the possibility of rapid, close to patient testing. The UK Government has established a process for the evaluation of such tests: https://www.gov.uk/government/publications/covid-19-evaluation-of-commercially-available-diagnostic-products/guidance-for-industry-on-evaluations-of-diagnostic-products-for-coronavirus-covid-19. and is providing grants to companies developing such technologies. The development of rapid diagnostic tests will need to address the question of sensitivity – rapid bedside testing for influenza virus has been used for screening purposes for several years but the high false-negative rate of these tests hampered patient care and limited public health disease control measures during the 2009-2010 pandemic, resulting in the reclassification of these from Class I tests (tests with low risk to public health requiring limited monitoring) to Class II devices in the USA24. Class II devices require special controls, examples of which include performance standards, post-market surveillance, patient registries, guidelines, design controls, and other appropriate actions to mitigate risk.
Antibody Testing:
The detection of an immune response to COVID-19 (serology) allows an understanding of who has been exposed (and been infected) and the degree to which individuals may have some immunity to future infections; this also facilitates better understanding of the spread of infection (as it has potential to identify asymptomatic infections). In similar viruses, the Spike (S) protein used to bind to host cells is immunogenic and the Receptor Binding Domain is the target of neutralizing antibodies25. However, there are a number of important questions yet to be answered including:
What is the cross-reactivity of immunoglobulins produced after infections with other coronaviruses (specificity)?
What proportion of infected individuals makes antibodies to SARS-CoV-2?
What magnitude of antibody response confers immunity?
How long does this immunity last?
Do previous Coronavirus infections influence the ability to generate antibodies to SARS-CoV-2?
Do previous Coronavirus infections provide some cross-protection from SARS-CoV-2?
This is a very exciting (if early) area of research and tremendous progress has been made, for example in the invention of detection methodologies for antibodies specific to SARS-CoV-226. However, it is important to remember that these tests are not suitable for acute diagnosis as it may take seven to ten days to seroconvert; equally, currently available assays may detect antibodies but may not provide evidence of immunity. Therefore, the full clinical utility of such tests remains to be established by further clinical research.
Viral and Antibody Kinetics in COVID-19
Limited information from case assessments investigating viral load kinetics have suggested that viral load increases post exposure reaching a peak at or shortly following onset of symptoms27,28. More severe illness is associated with higher viral load (1 log order higher) than in patients with milder disease. Viral load generally declines over a 10-15 day period post symptom onset, but may be sustained, and at higher level, in subjects developing severe pneumonia/ARDS29. The pattern of viral load dynamics is similar to influenza infection, implying that antiviral therapy given earlier in the disease course may prevent later complicated disease. This has implications for the design of clinical trials with antiviral therapies.
A recent series investigating antibody to SARS-CoV-2 viral proteins demonstrated that rising antibody levels can be detected from approx. day 7 of illness with most patients seroconverting within 14-21 days of onset. IgG and IgM antibody levels against the SARS-CoV-2 internal nucleoprotein and the surface spike receptor-binding domain correlated with neutralizing activity30.
Current Treatment
There are, currently, no specific antiviral therapies available for the treatment of COVID-19. Treatment of disease is currently supportive management based on first principles of respiratory support and management of complications.
Supportive Treatment
In the absence of specific interventions or availability of convalescent serum, management of COVID-19 is limited to the alleviation of symptoms, oxygen, continuous positive airways pressure and in more severe cases with ARDS and/or impending respiratory failure ventilatory support or exogenous corporeal membrane oxygen therapy. Approx 15-33% of COVID-19 affected hospitalized cases develop acute respiratory distress syndrome (ARDS). Factors that increase the risk of developing ARDS and death (which may occur in 40-50% of affected cases) include older age, neutrophilia, elevated lactate dehydrogenase level, CRP and D-dimer level and reduced platelet count.
Management of ARDS
Low tidal volume, plateau-pressure-limited mechanical ventilation is the primary treatment that has been shown to reduce mortality from ARDS. Tracheal intubation before the start of ventilatory support is a high risk, critical procedure in patients with COVID-19. Healthcare staff must apply the SAS principles: Safe – for staff and patient; Accurate – avoiding unreliable, unfamiliar or repeated techniques; Swift – timely, without rush or delay. Low tidal volume, plateau-pressure-limited mechanical ventilation is the primary treatment that has been shown to reduce mortality. Tidal volumes should be targeted to a lung-protective range (4-6 ml/kg ideal body weight). Informal reports from Italy and Singapore suggest that the driving pressures required are not very high, that patients require positive end pressures (PEEP) and respond well to prone ventilation. This suggests that the primary pulmonary pathology is likely to be small airway closure and atelectasis, rather than reduced lung compliance. Complications of ventilation include pneumothorax, ventilator-associated pneumonia, multiple organ failure, and, in the longer term, pulmonary fibrosis with prolonged respiratory failure.
Extrapulmonary Manifestations
Hepatic dysfunction (elevated transaminases) has been reported in 14% to 53% of patients in case series, more commonly in patients with severe disease. Evidence suggests that clinically significant liver injury is uncommon.
Cardiac injury is reported in 7% to 13% of patients in case series, with higher prevalence in patients who are severely or critically ill. Myocardial injury has been reported in > 25% of patients who are critically ill, and presents in two ways: acute myocardial injury and dysfunction on presentation or myocardial injury that develops as the severity of illness worsens. Arrhythmias have been reported in 16% of patients in case series. Fulminant myocarditis has been reported while cardiomyopathy has been reported in 33% of critically ill patients. It is unknown whether it is a direct cardiac complication of COVID-19 or due to overwhelming clinical illness. The long term consequence of infection on cardiovascular health is unknown.
Acute kidney injury (AKI) has been reported in 3-8% of cases, mostly those with other complications requiring ICU support: early recognition is important as AKI is associated with inpatient mortality >20%.
Disseminated intravascular coagulation is a feature in 71% of patient dying from COVID-19. It is frequently associated with other complicated illness in ICU.
As with any viral infection affecting the lungs, secondary bacterial infection and sepsis may further complicate the course of illness31. Elevated procalcitonin may enable earlier recognition of this potential and appropriate, early, use of antibiotics32.
Convalescent Serum
Convalescent serum is a strategy that has been exploited previously in novel infectious disease and is being explored in clinical trials. This approach has been reported to be effective in patients with SARS and MERS33,34. In a retrospective analysis use of convalescent plasma in SARS patients in Hong Kong, treatment was associated with a significantly reduced mortality and higher clinical success rate (defined as the proportion leaving the hospital by day 22) compared to those receiving only corticosteroid therapy35. Patients receiving convalescent plasma after day 16 fared no better than those receiving steroid alone35. With rising numbers of COVID-19 patients, consideration should be given to the preparation of convalescent plasma/serum from affected subjects for use in patients requiring hospitalization for more severe disease.
Conclusions
The emergence and rapid spread of SARS-CoV-2 represents a major emerging health threat to countries and populations around the world. Currently countries are enforcing public health measures designed to reduce spread of the disease within the population. Evidence from countries affected early in the outbreak suggests that these will successfully control spread, but comes with significant population disruption and potential for adverse effects on the world economy. An enormous effort is ongoing to understand the disease pathogenesis and to convert that understanding to the rapid scale up and production of therapeutic and prophylactic approaches to protect exposed populations. A range of promising avenues has been identified and will be discussed in the next chapters. In the interim, convalescent plasma/serum may offer an early approach to the specific management of disease in patients requiring hospitalization.
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