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Rethinking the vaccine landscape
Infectious diseases, which are those caused by pathogenic microorganisms such as viruses, bacteria, parasites, or fungi, have threatened humanity throughout history and are one of the leading causes of death worldwide.1 This is especially the case in low-income countries, often due to the consequences of poverty such as poor nutrition, sanitation, and lack of health education. With the exception of clean, safe water, vaccines are considered one of the best prophylaxes to combat infectious diseases, minimize or prevent transmission, and reduce mortality rates.
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Equipping Ourselves with Tools to Tackle Infectious Diseases
Immunization can protect against many infectious diseases including tetanus, measles, and influenza, and mass vaccination programs have proven successful in controlling or even eliminating infectious disease. For example, smallpox, which was once considered one of the deadliest diseases known to humans, has been successfully eradicated thanks to vaccination.2 Other diseases, such as wild polio, have been eradicated from most continents following multinational public health efforts to end virus circulation through vaccination.
In addition to the aforementioned infectious diseases, novel and unexpected infectious diseases periodically emerge, often with devastating consequences to human health. The latest example is the current COVID-19 pandemic caused by the SARS-CoV-2 virus, which has not only highlighted the rapid and devastating impact that an emerging infectious disease can have on global health, but also the need to accelerate the development of an effective vaccine once an outbreak has been detected.
Dr. Sanjay Garg, Senior Expert Scientist and Platform Head - Vendor Management, R&D Global Operations at Sanofi Pasteur, explained that it is often a race between the pathogen and the human when a new infectious disease emerges. However, he notes that with the advent of new technologies and platforms via innovation, we will be combating pathogens much faster and more effectively in the future.
In this article, we hear from Dr. Garg about the current direction vaccine development is taking, potential hurdles researchers and manufacturers might face, and how lessons learnt from COVID-19 will be shaping the future of vaccine development.
New Versus Traditional Modalities
Vaccines are biological products that provide active acquired immunity to a particular infectious disease. To achieve this the vaccine must contain antigens or genetic information to produce the antigen, either derived from the pathogen or produced synthetically, that induce immune responses to provide protection. There are several different types of vaccines available, but all work on the same principle – to stimulate an immune response that can protect against future infection.
Traditionally, vaccines were either classified as live attenuated (those which contain live pathogens that have been weakened or altered), or inactivated (those which contain whole pathogens that have been killed or altered so that they cannot replicate). In addition, several new platforms have emerged over the past few decades, including subunit, viral vectors, nucleic acid-based RNA and DNA vaccines, and virus-like particles. The different types of vaccines are listed in Table 1.
Table 1: Types of vaccine and which pathogens certain vaccines are licensed
| Type of vaccine | Licensed vaccines using this technology |
|---|---|
| Live attenuated (weakened or inactivated) | Measles, mumps rubella, yellow fever, influenza, oral polio, typhoid, Japanese encephalitis, rotavirus, BCG, varicella zoster |
| Killed whole organism | Whole-cell pertussis, polio, influenza, Japanese encephalitis, hepatitis A, rabies |
| Toxoid | Diphtheria, tetanus |
| Subunit (purified protein, recombinant protein, polysaccaride, peptid) | Pertussis, influenza, hepatitis B, meningococcal, pneumococcal, typhoid, hepatitis A |
| Virus-like particle | Human papillomavirus |
| Outer membrane vesicle | Group B meningococcal |
| Protein-polysaccharide conjugate | Hemophilus inflenzae type B, pneumococcal, meningococcal, typhoid |
| Viral vectored | Ebola |
| Nucleic acid | SARS-CoV-2 |
| Bacterial vectored | Experimental |
| Antigen-presenting cell | Experimental |
The research and development of a new vaccine typically takes between five and ten years and there are many steps involved in bringing a vaccine from bench to bedside. Following initial development, vaccines go through three phases of clinical trials before they are granted marketing authorization or approval by regulatory agencies. “The main criteria to move a candidate vaccine forward is that it is safe, effective, and immunogenic – the safety and quality of the product is a primary concern for the regulators,” affirmed Dr. Garg. He added that other key criteria include whether production and scale up capabilities can be managed and put in place.
While typically long timelines for vaccine development are necessary to meet safety and quality criteria, these timelines are very challenging to meet the demands during regional or global outbreaks or a pandemic. This can again be illustrated by SARS-CoV-2, where the only potential way to successfully control the impact of the virus was to immunize a critical mass of the world’s population. “During the pandemic, we have seen that there are new technologies that can accelerate this whole process,” said Dr. Garg, adding that the mRNA platform is a prime example of one such technology.
A huge advantage of the mRNA platform is that it is highly versatile, and candidate vaccines are relatively quick and easy to adapt and produce in the case of an emerging pathogen. Indeed, two COVID-19 vaccines (Pfizer/BioNTech and Moderna) were rapidly developed using mRNA technology, demonstrating acceptable safety profiles and high efficacy. Both vaccines were initially given Emergency Use Authorization (EUA) by the US FDA, and in August 2021 – just 17 months after the WHO declared COVID-19 a pandemic – Pfizer/BioNTech’s vaccine became the first to receive full approval.3
“Over a period of time, the regulators were able to gather more data on the safety and immunogenicity of the vaccine,” explained Dr. Garg. “This takes time – they have to look at the broader dataset and long-term safety profile of these new technologies before making decisions.”
Dr. Garg noted that the mRNA platform showed significant benefits in a pandemic scenario. “Only time will tell whether these technologies can be applied to existing vaccines that are on different platforms, such as recombinant proteins or inactivated viruses,” he said. “I am sure the regulators will be closely looking at the whole picture and what the risk-benefit is for moving currently licensed/existing vaccines to a mRNA platform.”
Avoiding R&D Bottlenecks
Regardless of its modality, manufacturing a vaccine is a complex journey and numerous bottlenecks can slow or halt progress during the research and development stages. From the research side, Dr. Garg explained that limited availability of adequate pre-clinical models and a lack of knowledge around how immune responses work are two key examples of rate-limiting factors.
Well-controlled human challenge studies, where participants are intentionally challenged with an infectious disease organism, whether they are vaccinated or not, can help to address this by providing unique insights into how viruses work and further understanding as to which promising candidate vaccine(s) offers the best chance of preventing infection. Increased emphasis on basic research is also helping mitigate some of the limitations associated with understanding the mechanism of action and subsequent protection.
Dr. Garg also highlighted the importance of assays in the early stages of research and development. “Assays are the lenses by which you can see how the candidate or approved vaccines are working,” he said. “The data generated support both the safety, efficacy, and immunogenicity of the candidate vaccine.” However, assays need to be well characterized, qualified, and validated, which takes time, effort, and money. “At times that becomes the rate-limiting step, but there are efforts being put in place to improve these assays and automate them to get quicker answers without compromising the quality of the data.”
From the production side, one of the critical hurdles to bringing a vaccine to market is the ability to scale up manufacturing to meet global demand. Fast, reliable, cost-effective, and good manufacturing practice (GMP)-compliant scale up from the clinical to commercial level is especially important at this stage. “The best approach is to think about scaling up the manufacturing process very early in vaccine development,” said Dr. Garg. “While the development and clinical studies are in progress, scale up of technology should be considered in parallel.”
Again, an example of this was where parallel efforts were put in place for the mRNA COVID-19 vaccine platforms. “That’s why, in a very short period of time, a large number of doses were generated, manufactured, and distributed,” he said. “The whole value chain of the vaccine development process has to be looked into to reduce these potential pitfalls.”
There are also logistical considerations associated with vaccine distribution, such as cold-chain management and transportation, especially when product temperature requirements are still to be established. “It’s never too late to start thinking about supply chain management, especially in countries where we do not have a good infrastructure in place to transport vaccines,” said Dr. Garg.
Before the COVID-19 pandemic, the storage temperature of mRNA vaccine candidates had not been given much attention. However, when the potential of these vaccines came to light, the associated cold chain challenges started to become apparent – Moderna’s vaccine had to be shipped at -20°C (-4°F), while Pfizer/BioNTech’s required shipment temperatures between -80°C and -60°C (-112°F and -76°F). “There are interventions in place to try and improve this, but it shows the importance of considering cold-chain maintenance in parallel to safety and immunogenicity testing,” said Dr. Garg.
Technologies that Dr. Garg believes have contributed to improved vaccine workflows include automation, AI and machine learning, and advances in genomics and proteomics. He explained that automation is an effective tool to support manufacturers in meeting the industry’s time-sensitive goals, while AI and machine learning provide deeper insights into data in shorter timeframes. Genomics and proteomics have already supported the discovery of various novel vaccine candidates, and Dr. Garg predicts they will aid efforts to discover candidates for challenging infectious diseases such as Malaria, TB, and HIV.
Learnings From COVID-19: Accelerating the Vaccine Development Process
The speed by which a COVID-19 vaccine was developed has demonstrated that the previously lengthy process can be accelerated; however, Dr. Garg cautions that this does not mean other vaccines will now be made on a comparable timescale. “If there’s one thing we take home from the pandemic, it is that some of the components of vaccine development and production can occur in parallel – they do not have to be sequential. But by speeding up a process, the two things we can’t compromise on is the safety and immunogenicity. We can’t cut any corners.”
He also suggests we should pre-emptively look into what other pathogens are out there for which we do not have a vaccine. “Why wait until we have a pandemic to start evaluating those technologies? I am sure that disruptive technologies like the mRNA platform will help with this, and I expect it to be another tool in our toolbox to tackle some of the emerging pathogens which are not currently a pandemic, but that may develop.”
Sanofi's R&D pipeline
Over half a billion people are vaccinated annually with Sanofi vaccines worldwide and Dr. Garg emphasizes that the company goes above and beyond to ensure these vaccines are safe and effective. “To implement that, there are a lot of checks and balances that are placed on quality assurance and monitoring, both on the product side but also during clinical studies,” he said. There are currently 11 vaccines in Sanofi's R&D pipeline,4 four of which are in Phase III, including a recombinant baculovirus vaccine developed in collaboration with GSK for COVID-19. “We have to collaborate and join forces to develop vaccines for emerging pathogens and disease-causing agents,” said Dr. Garg. “No singular entity or organization can do everything – every organization has their own expertise. As we have seen in the COVID-19 situation, everyone had to come together.”
Conclusion
While there is no one-size-fits all approach to tackling infectious diseases – one technology may work for one pathogen but not another – it is evident that new technologies will help encounter certain pathogens quicker and more efficiently than we have done to date. As a population, we may always be vulnerable to infectious diseases, but there are steps we can take to reduce research and development timelines without compromising safety and efficacy.
“If we continue to strive forward and make these efforts, it will hopefully keep us ahead of the bugs,” concluded Dr. Garg. “We need to be ready, and I’m sure that new technologies will help us achieve this.”
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.
Sources:
- The top 10 causes of death [Internet]. Who.int. 2021 [cited 13 December 2021]. Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
- Smallpox vaccines [Internet]. Who.int. 2021 [cited 13 December 2021]. Available from: https://www.who.int/news-room/feature-stories/detail/smallpox-vaccines
- FDA Approves First COVID-19 Vaccine [Internet]. U.S. Food and Drug Administration. 2021 [cited 13 December 2021]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine
- Sanofi Pipeline [Internet]. Sanofi.com. 2021 [cited 13 December 2021]. Available from: https://www.sanofi.com/en/science-and-innovation/research-and-development/rd-pipeline
The information in this white paper reflects Dr. Sanjay Garg’s views on this topic and should not be taken as representing Sanofi Pasteur.
Revvity Inc. does not endorse or make recommendations with respect to research, medication, or treatments. All information presented is for informational purposes only and is not intended as medical advice. For country specific recommendations, please consult your local health care professionals.