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Disclaimer: The information in this white paper reflects Dr. Sanjay Garg’s views on this topic and should not be taken as representing Sanofi Pasteur.
Typically, it takes 5-18 years and costs $200-$500 million to develop a vaccine (Kis, 2018). It is a lengthy, complex process with a high failure rate; few candidates successfully proceed from the early stages of discovery to approval and manufacturing (Lurie, 2020). To ensure safety throughout research and development, vaccine developers have historically employed a sequential process, marked by frequent pauses for data analysis and quality improvement (Lurie, 2020).
However, that changed when the Severe Acute Respiratory Syndrome–coronavirus 2 (SARs-CoV-2) spread in late 2019 and early 2020. With millions of people worldwide contracting coronavirus disease 2019 (COVID-19), vaccine developers faced the enormous challenge of producing a safe, effective vaccine in months, not years, to stop the spread of the deadly disease.
As a vaccine expert, Sanjay Garg, Ph.D., Senior Expert Scientist and Platform Head, Vendor Management R&D Global Operations, Sanofi Pasteur, has studied vaccine development for two decades. He followed his academic research training at Emory University, Atlanta, GA, with experience at the Centers for Disease Control and Prevention, also in Atlanta. He has witnessed vaccine research as a process and clinical development over the years.
According to Dr. Garg, the pandemic is changing vaccine development today and in the future. Through collaboration, not competition, stakeholders share the common goal of countering the virus infection and providing long-term immunity.
The slow, linear, methodical process of the past is being reconstructed. In the sprint to protect the public's safety, clinical trial phases overlap instead of occurring sequentially. In the New England Journal of Medicine, Coalition for Epidemic Preparedness Innovations (CEPI) advisor Nicole Lurie, M.D., and colleagues plotted the difference between traditional vaccine development and a pandemic paradigm (Lurie, 2020). In the new paradigm, preclinical studies may occur in tandem with first-in-human studies. Phase 1 may intersect with Phase 2. And Phase 2 may crossover into Phase 3.
According to Dr. Garg, when initial results show promise, decisions are being made for mass distribution, manufacturing large quantities at risk in parallel with Phase 3 studies. He also emphasized the importance of conducting post-marketing Phase 4 studies to continue data gathering and analysis.
To make the most of each day of research, developers must harness all the technology available to increase speed without reducing safety. Artificial intelligence can expedite many aspects of clinical research, according to Dr. Garg.
Adaptive clinical trials can leverage insights from accumulating data to make prospective changes in trial design (Harrer, 2019). Machine learning can help streamline efficiency in patient recruitment, enrollment, and monitoring (Harrer, 2019).
As of October 2020, 44 COVID-19 vaccine candidates were in clinical evaluation, with another 154 in preclinical evaluation (World Health Organization, 2020). The COVID-19 vaccine candidates include protein- and virus-based approaches (van Riel, 2020). Recombinant protein or virus-like particles mimic the virus's structure, but the lack of a viral genome prevents them from replicating, improving the safety profile compared to live viral vaccines (van Riel, 2020). While the virus-like particle vaccine has proven successful over time in protecting against smallpox and HPV, they take longer to produce (van Riel, 2020). They must be grown under strict conditions with extensive safety testing.
Newer viral-based approaches offer the advantage of speed but have yet to be time-tested in humans. Viral vector vaccines carry DNA containing virus-encoded antigens into the cells to stimulate an immune response (Corey, 2020). Two of three vaccine candidates in Phase 3 clinical trials in the United States use this approach (World Health Organization, 2020):
Other next-generation vaccines use nucleic acid, both DNA and RNA. These types of vaccines are easy to design and produce but are not without challenges. DNA-based vaccines, when administered intramuscularly have reduced immunogenicity (van Riel, 2020) (Brisse, 2020). Therefore, alternative delivery systems are under review using electroporation (Corey, 2020) (Brisse, 2020). RNA-based vaccines show higher immunogenicity than DNA vaccines. RNA vaccines can be designed in many ways to activate an immune response. Messenger RNA (mRNA) vaccines use lipid nanoparticles to protect and deliver the molecule (Corey, 2020). Of the multiple mRNA COVID-19 vaccines under investigation, one has entered Phase 3 clinical trials in the USA (van Riel, 2020) (World Health Organization, 2020):
Should one of these newer vaccine designs succeed in containing the spread of COVID-19, it could serve as a milestone achievement in terms of time and technology.
"To shorten the timelines of clinical research, we need to have a good science base for vaccines," said Dr. Garg.
A rational approach to vaccine development can increase speed and reduce costs by concentrating on the most prolonged vaccine development phase—discovery and target validation (Brisse, 2020). Systems thinking can help researchers understand the mechanisms underlying pathogenesis and characterize the effect on the immune system (Dhillon, 2020).
He described an integrated system with a holistic perspective of immune response that integrates genomics, transcriptomics, and proteomics—backed up by artificial intelligence and bioinformatics.
"New technology with multiplexing infrastructure is needed to look into how the virus is tracking with the immune system at the cellular level," said Dr. Garg.
High-throughput technology can accelerate immune profiling and vaccine development (Oberg, 2011). Transcriptomics provides insights on the biomarkers of response to a vaccine. Traditional histology for humoral and cellular responses identifies and quantifies subsets of cells involved in the immune response like antigen-specific B cells and T cells (van Riel, 2020). Recent advances in flow cytometry, such as imaging flow cytometry and multi-parameter flow cytometry offer even greater capabilities. Flow cytometry data can be integrated with gene expression, serum cytokine levels, virus titers, and ELISPOT data to identify those who will and will not respond to a vaccine (Pezeshki, 2019). RNA sequencing reveals immune cell development and regulatory networks to predict immune function (Cotugno, 2019).
To explore the mechanisms leading to a successful vaccine, proteomics supports the study of immune response effectors like proteins, antibodies, and cytokines. Traditional methods of ELISA and Western blot limit the number of proteins that can be studied. However, mass spectrometry-based proteomics defines the major histocompatibility complex (MHC) in the context of T cell profiling and antigenic B cell activity (Cotugno, 2019).
To analyze the large data sets, Dr. Garg says bioinformatics experts need to be added to the team to visualize and interpret data. Simultaneously, artificial intelligence can develop models to analyze multi-assay data, predict immune response, and validate data.
The multidisciplinary nature of future vaccine development teams also includes supply, manufacturing, and logistics.
"An mRNA vaccine has to be formulated and transported in a frozen state," said Dr. Garg. In parallel with vaccine development, a company must build infrastructure that includes freezer farms to support distribution to even the most remote communities.
In the face of the most severe threat to public health in a century, industry, academia, and government have come together with urgency and dedication. Organizations like the Biomedical Advanced Research and Development Authority (BARDA), CEPI, and WHO have rallied to expand countries' capacity with public-private partnerships to develop, manufacture and distribute vaccines and other biologics to counteract the pandemic. The U.S. Department of Health and Human Services joined forces with AstraZeneca to make 300 million doses of a vaccine available by January 2021 (U.S. Health and Human Services, 2020). AstraZeneca partnered with the University of Oxford to develop the vaccine candidate (AZD1222) (U.S. Health and Human Services, 2020).
"Leading manufacturers are collaborating and licensing technology from early phase biotech companies," said Dr. Garg. "We have collaborated with another big pharma company with the objective of having a vaccine in place." (Sanofi Pasteur and GlaxoSmithKline are combining technology in the development of a recombinant protein vaccine candidate funded by BARDA.)
Unprecedented levels of collaboration are occurring at every level. At pharmaceutical and biotechnology companies, virtual cross-functional teams with representation from senior leadership, research and development, manufacturing, regulatory, informatics, and marketing collaborate in real-time with broad access to information.
Immunogenic vaccines are fundamental to public health. "Partnerships with government, industry, and academia are needed. We can't do it alone. No one can claim it all. It is about collaboration," said Dr. Garg.
To strengthen preparedness for future pandemics, Dr. Garg stresses the need for science-focused vaccine development programs in academia and industry, with a broader perspective. "We have to take a wider view. We have to stop looking at only the obvious pathogens," said Dr. Garg. "COVID-19 has shown us that we need to look into other, riskier pathogens with the potential to be pandemic in nature."
As early as March of 2020, the WHO outlined a blueprint to develop cross-cutting research and development preparedness for disease "X," a currently unknown pathogen capable of causing another international epidemic (World Health Organization, 2020). In its call-to-action, the WHO stated that preparedness requires an understanding of immunity and pathophysiology with serological testing and assays that monitor response to treatment and prognostic markers. Furthermore, the global health agency prioritized access to reagents such as virus isolates, panels of clinical samples, research reagents, and quality control reagents (World Health Organization, 2020). While current scaled-up innovation focuses on restructuring vaccine development for COVID-19, it is also intrinsically about creating a new era in vaccine development.
Dr. Sanjay Garg is a biopharmaceutical leader with over two decades of industrial and academic experience in pre-clinical and clinical development of human vaccines and therapeutic human monoclonal antibodies - with broad expertise in analytical techniques, biomarker development strategies, project management and operational effectiveness. Since late 2019, he has served as head of Vendor Management within Sanofi Pasteur R&D Global Operations, where he leads the platform for the identification, selection and onboarding of external testing partners and CROs to support clinical development of vaccines.
Prior to leading Vendor Management team, Dr. Garg has served in various roles at Sanofi and Sanofi Pasteur since early 2007, most recently as Senior Expert Scientist - contributing to strategic leadership by providing direction to leverage company capabilities for pre-clinical, translational and clinical development of vaccines; and as Director Innovation and Technology - Virology Platform and Director Translational Medicine, Immune Mediated Diseases (IMD) Clinical, Sanofi-Genzyme R&D Center.
Dr. Garg completed his associate service fellowship at the Centers for Disease Control and Prevention (CDC), Atlanta, GA studying effects of different TLR ligands in inducing maturation of murine bone marrow derived dendritic cells. He also evaluated humoral and cellular immune responses generated by human adenovirus-based Influenza vaccine. Dr. Garg completed his post-doctoral fellowship in Microbiology and Immunology at Emory University, Atlanta, GA where he analyzed the class of antigen presenting cells involved in generation of immune response after gene gun mediated delivery of DNA vaccines using ROSA26R mice and Cre-LoxP system for in vivo marking and tracking of Dendritic cells.
While working as Research Associate at National Institute of Immunology, New Delhi, India, Dr. Garg analyzed the role of mucosal micro-environmental factors that may trigger immunogenic or tolerogenic signals that might allow for preferential commitment of B cells and T cells to effectors or memory pathway.
Dr. Garg has a PhD in Microbiology from All India Institute of Medical Science (AIIMS), New Delhi, India and MTech in Biotechnology from Indian Institute of Technology (IIT) Kharagpur, West Bengal, India.