By Dean Giovanniello, RPh., Vice President; Rebecca Podolsky, Senior Analyst; Holger Müller, Vice President; Balazs Felcsuti, Vice President; and Carrie Jones, Vice President
Viral diseases continue to emerge and represent a serious threat to the global public health. Over the past 20 years, several epidemics such as the severe acute respiratory syndrome (SARS) in 2002/2003 and the H1N1 influenza in 2009 have been recorded. Currently, the world is gripped by the COVID-19 pandemic, triggered by the coronavirus SARS-CoV-2, which seems to be highly contagious and has spread quickly around the globe. At the time of this writing, almost 4MM cases have been diagnosed globally with more than 270,000 deaths1. With no specific treatment option currently recommended or available, the pharmaceutical industry has launched an unprecedented effort to provide a prophylactic or therapeutic treatment option.
Vaccines are a promising prophylactic treatment but may be years away
Vaccines are currently regarded as the most promising prevention opportunity and will represent a critical step in the return to normalcy by helping to establish “herd immunity.” Vaccines can quickly confer immunity to large numbers of healthy people, preventing rapid spread of the disease and offering protection to high-risk groups by virtue of the immunity of those they meet.
As of May 8th, over 110 different COVID-19 vaccines are in development worldwide2 and coordinated efforts have been initiated to shorten development timelines. The FDA’s Center for Biologics Evaluation and Research (CBER) has pledged to facilitate the development of COVID-19-directed treatment by providing regulatory flexibility, advice, guidance, and technical assistance3. In addition, a public-private partnership with the NIH called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)4 may provide expertise, financial support, and collaborative framework for those companies developing vaccines. Also, novel technologies in vaccine manufacturing can shorten the development timeframe as has been pointed out in a recent Health Advances blog. However, due to the stringent clinical trial requirements and regulations on vaccines, the development time for an effective SARS-CoV-2 vaccine may be more distant than some make us believe. SVB Leerink analyst Geoffrey Porges estimates that a vaccine may not be available for several years5. Estimates by Wall Street analysts supported by computer-generated models predict timelines of up to five years. If history is anything to go by, the average development timeline for a new vaccine is even closer to 10 years, and the probability of market entry is as low as 6%6.
Rationale for Protective Antibodies as Prophylaxis and Treatment
While there is a distant possibility that vaccine therapies may become available in the nearer-term, it is more likely to assume that projections of 12-18 months until market entry may be too optimistic. Therefore, alternative approaches are needed to treat currently infected moderate-severe COVID-19 patients and to offer prophylaxis to risk-high groups like first responders, and eventually, even to the general population.
“Convalescent plasma has historically been used therapeutically and for prophylaxis” — as prevention — “typically in times when a new disease, virus, bacteria comes on the scene and we don’t have any viral-specific therapies for that new or novel disease,” said Dr. Erin Goodhue, executive medical director of the American Red Cross.
Therapeutic antibodies derived from convalescent patients could provide a more timely solution. Therapeutic antibody therapy was first performed over a century ago and is used in clinical practice today for hepatitis A and B, rabies, and respiratory syncytial virus (RSV)7. During the last large-scale global pandemic, the 1918 Spanish flu8, it is believed that antibody therapy greatly reduced the mortality rate. Furthermore, its use has been shown to be effective in coronaviruses similar to COVID-19 such as SARS19. Early results from hospitals using plasma from recovered COVID-19 patients have also shown promise. A small study of 10 severely ill patients treated with convalescent plasma in Wuhan, China, showed improved outcomes over a sex- and age-matched historical control. However, the applications of antibody therapy extend far beyond treatment—antibodies can also be used in healthy patients to prevent infection. The applicability of passive immunization through antibodies was also investigated in a widespread indication such as influenza in a recent article, where the authors concluded that the concept “could be used as pre- or post-exposure prophylaxis to prevent or reduce symptoms or in the treatment of severe influenza infection.”10
How does antibody therapy work? A convalescent patient’s blood contains immunoglobulins, or antibodies, that the patient formed to fight against the coronavirus. The patient’s serum or plasma may be transfused directly to another patient, or the coronavirus-specific antibodies can be isolated and concentrated to form hyperimmune globulins which are administered intravenously to confer passive immunity. When the antibodies encounter the virus, they may either target and destroy the virus directly, or stimulate specialized immune cells to attack the virus and offer a therapeutic- or prophylactic benefit.
Figure 1: Schematic Principle of Convalescent Antibody Therapy
What is Required to Enable Protective Antibody Therapy?
According to the recent article published in the Journal of Clinical Evaluation11, “to deploy convalescent serum administration for COVID-19 the following six conditions must be met: (i) availability of a population of donors who have recovered from the disease and can donate convalescent serum; (ii) blood banking facilities to process the serum donations; (iii) availability of assays, including serological assays, to detect SARS-CoV-2 in serum and virologic assays to measure viral neutralization; (iv) virology laboratory support to perform these assays; (v) prophylaxis and therapeutic protocols, which should ideally include randomized clinical trials to assess the efficacy of any intervention and measure immune responses; and (vi) regulatory compliance, including institutional review board approval, which may vary depending on location.” So, where do we stand on these six conditions across geographies?
- With almost 4MM12 COVID-19 patients have been registered worldwide with varying degrees of patient recovery rates, ranging between 94% for China to 17% for the US, reflecting different approaches to testing, patient tracing, and the evolutionary stage of the pandemic in the respective local region, among other factors. This patient pool hasn’t gone unnoticed and the American Red Cross13 together with the FDA has started an appeal to collect convalescent plasma. Similar initiatives can be observed in Europe.
- Worldwide, more than 110MM14 blood donations are collected annually, about 100MM of which as whole blood and about 12MM donations are plasma collected via apheresis. Processing this amount of blood donations suggests that the necessary infrastructure is in place to effectively and safely collect convalescent COVID-19 plasma. With about 25% of global blood donations processed in Europe, the old continent may be slightly better positioned compared to the rest of the world.
- Assay availability is critical to accurately identify convalescent donors and over the last months around 60 tests15 have been approved by different regulatory agencies. While most of the tests are PCR-based with focus on the identification of COVID-19 patients, antibody tests have also become generally available across all geographies but questions on reliability continue.
- The availability of testing facilities has been a point of debate during the COVID-19 pandemic and a recent blog from Health Advances highlighted the shift towards decentralized testing capabilities to allow for a faster response to a pandemic. However, during the COVID-19 crises, the installed base of testing capacity has never been questioned, rather the availability of the appropriate assays.
- At the time of writing, more than 40 clinical studies have been initiated in all major geographies applying an antibody focused approach, and 14 of these use convalescent COVID-19 plasma16 but given the early stages of the clinical development, it will still require additional scientific and clinical confirmation before robust protocols for treatment and prophylaxis have been established.
- Regulatory agencies in the US17, Europe18 and China19 have been quick to realize the beneficial potential of IgG antibody therapies and have established directives that govern all aspects from collection to administration of these therapies, however at present focused on a therapeutic application.
Figure 2: Six Test Assessment by Geography
Applying the six tests to the United States, Europe, and China, suggests that all three regions should be well-positioned to manufacture and distribute convalescent-plasma derived antibody therapies. However, one glaring gap is detailed treatment protocols do not exist in any geography but should become available, together with the approval of the corresponding prophylactic and therapeutic options.
Therapies in Development
At the time of writing, more than 300 COVID-19 focused therapeutics are in development and more than 40 projects involve antibody therapies, including recombinant- and plasma-derived approaches.
Figure 3: COVID-19 Targeted Development Pipeline
Many of the plasma-focused development projects involve collaborations across multiple geographies. Grifols SA, the Spanish drugmaker, is teaming up with the U.S. Biomedical Advanced Research Development Authority, the U.S. Food and Drug Administration, and other Federal public health agencies to develop plasma-based therapies. Grifols and the health agencies will process the collected plasma into a hyperimmune globulin, or HI-G, and support the necessary preclinical and clinical studies to determine if anti-SARS-CoV-2 HI-G therapy can be used to treat COVID-19. The company said it is volunteering its resources in plasma collection using FDA-approved plasma donor centers. It will test and qualify donors with the help of the other health agencies and process plasma into HI-G and conduct studies to determine whether HI-G made from the plasma of recovering donors can be a viable treatment for the disease. An even broader consortium has been established between Australia’s CSL, Japanese Takeda, and European firms Biotest, BPL, LFB, and Octapharma to develop a plasma-based therapeutic. The global nature of the alliance has been established with the specific goal to establish sustainable and scalable infrastructure for the manufacture and distribution of plasma-based therapies. However, with the required number of IgG-antibodies unknown to reach immunity in patients, the availability of sufficient plasma donations remains unclear.
A novel approach, that could directly address potential supply issues of plasma-based therapies, is called rCIG (recombinant anti-coronavirus 19 hyperimmune gammaglobulin) and is pursued by GigaGen. This approach uses single-cell sequencing to “capture and recreate” whole libraries of antibodies from recovered COVID-19 patients. The company can then choose which of those antibodies to turn into recombinant polyclonal antibody treatments in a method that does not rely on collecting vast amounts of plasma from many donors. Although rCIG could be given as a prophylactic, it is seen as a therapeutic since it must be given to patients intravenously. This method is much more scalable than plasma-based methods, since one person’s B cell repertoire can be used to generate a drug that treats millions of patients. “The ability of the platform to capture and replicate complete antibody libraries from recovered patients … has the potential to overcome challenges related to supply shortages, which is an ongoing problem for plasma-based therapies… ” the company said in a recent press release20. Additionally, due to their recombinant nature, GigaGen’s recombinant polyclonal therapies have a decreased risk of contamination and are consistent from batch to batch, enabling a controlled dosing protocol. As promising as this sounds, rCIG will not enter clinical trials until early 2021.
Plasma-derived antibodies have been used throughout the history of pandemics and may be a valid treatment option as they can be readily available and have long played a role in conferring immunity to viruses. Plasma-based therapy development represents a near-term opportunity, based on the existing collection, processing, and delivery infrastructure. Additionally, regulatory paths have been established by the FDA, EMA and NMPA that will put the development on a reliable regulatory path. Questions remain as to whether the antibody titer required to achieve COVID-19 immunity and the duration the COVID-19 specific immunity can be maintained. Newer innovations such as rCIG derived antibodies may be a longer-term option but have the capability to circumvent any potential shortages of much-needed convalescent plasma while offering the possibility of significant production scale-up.
|About the Authors|
Dean Giovanniello, RPh., Vice President, co-leads the Health Advances Biopharma Launch Excellence practice, with sector expertise in commercial development, including brand and launch strategy/planning/KPI’s, portfolio management and asset valuations in the emerging biopharma and medtech industries.
Rebecca Podolsky, Senior Analyst, is experienced in commercial strategy, market research and analysis, and due diligence within biopharma, diagnostics, and medtech.
Holger Müller, Vice President, co-leads Health Advances European office and is a leader in the firm’s Biopharma Practice, focusing on Cardiovascular, Immunological, and Respiratory diseases.
Balazs Felcsuti, Vice President, is a leader in the firm’s Biopharma Practice focusing on Autoimmune and Gastroenterology diseases.
Carrie Jones, Vice President, is a leader in Health Advances’ Orphan Drug practice, assisting biopharma clients advance novel therapeutics across the product lifecycle, from developing targeted portfolio strategies to defining efficient and effective product development and commercialization strategies.
|About Health Advances Biopharma Practice|
Our Biopharma team of scientists, physicians, and commercial industry experts has a deep working knowledge of the healthcare industry and its stakeholders. We tackle the challenges of drug development, market access, and commercialization. Our teams partner with clients to create strategies that guide their most critical business decisions using our clinical, technical, and business perspectives.
For more information, please visit https://healthadvances.com/biopharma/.
 Worldometers.info, accessed May 8, 2020, available at https://www.worldometers.info/coronavirus
 Pharmaprojects, accessed May 8, 2020
 FDA letter to sponsors, April 30, 2020, available at https://www.fda.gov/vaccines-blood-biologics/industry-biologics/coronavirus-covid-19-cber-regulated-biologics
 NIH news release, April 17, 2020, available at https://www.nih.gov/news-events/news-releases/nih-launch-public-private-partnership-speed-covid-19-vaccine-treatment-options
 Sober-Up! 25 Reasons Not to Count on COVID vaccine for herd immunity in 1-2 years, SVB Leerink analyst note
 PLoS One, 2013, 8(3)
 Critical Care Medicine, 2010, 38, 66-73
 Ann Intern Med 2006, 145(8), 599-609
 Eur J Clin Microbiol. Infect Dis 2005, 1, 44-46
 Vaccine, 2016, 34(45), 5442-5448
 J Clin Invest 2020, 130(4), 1545-1548
 https://www.worldometers.info/coronavirus/, accessed on May 1, 2020
 www.redcrossblood.org, accessed May 1, 2020
Global Status Report on Blood Safety and Availability. WHO, 2016.
 FDA news release, March 19, 2020, accessible at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-facilitate-development-treatments
 Pharmaprojects, accessed May 8, 2020
 FDA guidance to Industry, updated May 1, 2020, accessible at https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma
 EMA programme of COVID-19 convalescent plasma collection and transfusion, April 4, 2020, accessible at https://ec.europa.eu/health/sites/health/files/blood_tissues_organs/docs/guidance_plasma_covid19_en.pdf
 NMPA, notice on issuance, April 3, 2020, accessible at http://www.nhc.gov.cn/yzygj/s7658/202003/61d608a7e8bf49fca418a6074c2bf5a2.shtml
 GigaGen press release, March 30, 2017