Author: Dr. Linda Morrow – March 25th, 2021
Imagine a pandemic without having to shut down our lives. Imagine governments and industry working cooperatively to develop diagnostic and vaccine platforms ready to be deployed. Imagine scientists around the world collaborating to share vital information crucial for the development of the next life-saving technology. These are visions of the future inspired by innovations springing from the COVID-19 global pandemic.
The global sweep and devastation of COVID-19 has turned the attention of the world onto vaccines. Laser-focused on combating the pandemic, governments, bilateral and multilateral organizations, NGOs, and the private sector have announced $39.5B in support of vaccine research and development since January 2020. This emphasis has been spectacularly successful: at the time of this writing, globally, 6 vaccines have been fully approved, 78 are in human clinical trials and an additional 77 vaccines are in animal testing; more than 420M doses of vaccine have been delivered world-wide. The development and approval of the first vaccines have taken only 9 months, which is an unprecedented speed of development. Despite the massive public and private combined investment in combating the pandemic, challenges and opportunities remain in reimagining vaccine production, reformulating the vaccines to address arising novel variants, and in accelerating the manufacturing of vaccines.
The first SARS-CoV-2 vaccines authorized for use in the US and the EU introduced a novel vaccine methodology, one taking advantage of advances in understanding the interactions between virus, host cells and immune defenses. While older vaccine technology uses whole viruses (either killed or live attenuated) or virus-like particles, the novel vaccines are composed of messenger RNA (mRNA) derived from the viral genetic code. The mRNA vaccine directs the host cell to produce key viral proteins that are responsible for infectivity, triggering the immune system to make antibodies to this very specific part of the virus (e.g., the spike protein of SARS-CoV-2) that prevent the virus from being able to enter host cells. While work on mRNA vaccines has been ongoing for many years, additional technical advances to package the mRNA for injection have made these new vaccines possible.
Messenger RNA vaccines are an important advance because they could allow for much more rapid vaccine production – once the genetic sequence of the virus is known, manufacturing of the mRNA is relatively straightforward, using in vitro transcription. Unlike the current 6-month process required each year to grow, purify, manufacture and test new influenza vaccines, this technique additionally allows rapid modifications in the vaccine to address novel strains. As both of the vaccines first authorized in the US and the EU are the first ever mRNA vaccines, the durability of the response and the protection that such specific antibodies might afford against novel strains of the virus are open questions. Following data showing persistence of neutralizing antibodies 119 days after dosing, most experts are anticipating at least 6 months of lasting immunity. Promising data suggest that even reduced neutralizing antibody activity against emerging strains may be adequate to provide protection, but more data are needed.
Other approaches to COVID-19 vaccines are designed to reduce cost, improve compliance or support widespread vaccine production. Oral and intranasal vaccines, with better patient acceptance, ease of administration and distribution are on the horizon with candidates from Merck, ImmunityBio, Vaxart (all oral) and Altimmune (intranasal) in the clinical pipeline. Tablet or intranasal formulations are unlikely to have the onerous temperature or handling requirements of the currently available vaccines. Medicago, a Canadian biotech firm, has developed a plant-based vaccine technology (virus-like particles grown in plants) that offers rapid production of clinical grade vaccine doses 6-8 weeks after receiving the antigenic viral gene sequence. The promise of such a plant-based manufacturing platform is the potential magnitude of dose scale up which could reach more than 1 billion doses per year.
Scaling vaccine manufacturing to meet the demand of the pandemic has presented a major hurdle to a global vaccination program. The inability of “rich” countries to manufacture vaccines at home (despite their scientific contributions to their development) has been a wake-up call. Currently the largest COVID-19 vaccine manufacturer in the world is Serum Institute of India (SSI), holding contracts with Oxford/Astra Zeneca, Codagenix, SpyBiotech and Novavax (although vaccines from the last 3 companies are not yet approved). Other companies in India and China are also in line to produce 100’s of millions of doses. At present, the bulk of the Moderna vaccine production is done in Massachusetts, while the BioNTech/Pfizer vaccine is being manufactured in multiple steps in specialized Pfizer facilities in the US, in Belgium and in BioNTech German facilities in Marburg. Establishing and maintaining adequate national manufacturing capabilities are key interests of many governments as the global community scrambles to create access and distribute enough vaccine for 7 billion humans and to be better prepared for a future pandemic.
Public-Private Partnerships, Global Initiatives
Countries around the world have responded with a wide range of initiatives to tackle the impact of SARS-CoV-2; some of these include governmental support of vaccine development and diagnostic testing, financial support of key industries, coordination of vital supplies, and streamlining of critical governmental approval processes for medications and vaccines. Arguably during this crisis, governments, through regulations and public health guidelines, should set the overarching vision and then provide financial follow-through to support key developments. This path has been followed to greater and lesser success. In Germany, the Federal Ministry of Education and Research (BMBF) COVID-19 initiative announced a special program (€750M) to support three companies working with different technologies to develop a vaccine: BioNTech, CureVac and IDT Biologika. The Canadian Government dedicated $2B to partner with Canadian companies to support the need for diagnostic testing, ventilators and protective personal equipment. Supported by $10B in government funding, Operation Warp Speed in the US was designed as a public-private partnership with 3 pillars: vaccines, diagnostics and therapeutics. While the bulk of Operation Warp Speed was directed toward vaccine development, accelerated development of testing for the virus also resulted. To date, the FDA has issued 223 emergency use authorizations for diagnostic tests for SARS-CoV-2 with the emphasis now on direct-to-consumer diagnostic testing that can be performed at home, in schools or at the workplace. Improvements in testing include alternative sample sites (nasopharyngeal, anterior nose, oropharyngeal, saliva, sputum), increased speed of results, improved reliability, and ease of use. An additional $12B in government funding in the US to support COVID-19 testing was just announced, along with the creation of a streamlined authorization path for COVID-19 screening tools.
While a variety of combined public-private collaborations have been successful in making headway against the pandemic, it has been widely recognized that without a viable global vaccination approach, the potential for ongoing viral mutation with the emergence of novel strains and persistence of the epidemic remains. The World Health Organization (WHO) along with Gavi (the international vaccine alliance), and the Coalition for Epidemic Preparedness Innovations (CEPI) are leading COVAX, an initiative to provide equitable access to vaccines around the world. COVAX plans an initial distribution of 330 million doses of vaccine to 145 countries in June 2021. COVAX is being supported in part by donations from wealthier countries, including the EU (€2.3B) and the US ($4B).
Global Scientific Collaboration
One of the most optimistic developments resulting from the pandemic has been the global cooperation of the scientific research community. On January 11, 2020, Chinese scientists submitted the gene sequencing data to Virological.org, an online forum which describes itself as “A discussion forum for analysis and interpretation of virus molecular evolution and epidemiology.” On January 12, 2020, only forty-two days after the first COVID-19 patient developed symptoms in Wuhan, the genetic sequence of SARS-CoV-2 was uploaded to GenBank, the National Institute of Health (NIH) genetic sequence database which contains all publicly available DNA sequences. There is no question that the early and widespread dissemination of this information led to the rapid vaccine development; the first Phase 1 clinical trial began just 10 weeks later.
Dr. Linda Morrow has spent more than 25 years in clinical research and drug development. She has been the principal investigator on 85 clinical research studies for metabolic small and large molecule therapies, biologics, biosimilars and devices. She served as Vice-President and Chief Medical Officer and board member at ProSciento, Inc. where she had oversight of CRO and scientific services for global multi-site clinical trials and clinical operations. Prior to her roles at ProSciento, Dr. Morrow was a faculty member at the University of Michigan Division of Geriatric Medicine and Harvard University’s Division on Aging. Dr. Morrow earned a medical degree from the Medical College of Pennsylvania (now Drexel University) and completed her post-graduate training at the University of Michigan. She is an author on more than 50 peer-reviewed articles and chapters.