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Advancing innovation and public health impact at GSK

AUTHORS Emmanuel Hanon, head of research and development at GSK Thomas Breuer, chief medical officer of GSK Vaccines Rino Rappuoli, chief scientist and head of external research and development at GSK Vaccines ADDRESS GSK, 20, Avenue Fleming, Building W23, 1300 Wavre, Belgium

ccording to the World SELECTING FUTURE mortality) and the average life Health Organization VACCINES expectancy was around 60 A(WHO), only access Disease burden (the public health years of age. Nowadays, families to clean drinking water rivals impact a disease has on a region tend to be much smaller and life vaccination in its ability to help or population) has the largest expectancies are around 80+ in save lives (around two to three influence on which vaccines are industrialized nations. However, million each year). For more pursued. This is often calculated as societies experience a growing than 200 years, scientists have in terms of quality-adjusted proportion of older adults, the been developing vaccines to life-years (QALYs) and costs; burden of disease is starting to address devastating diseases considering factors such as shift; of the more than 40,000 and help protect people of all disease frequency (is it common deaths from vaccine-preventable ages worldwide. However, public or rare), impact on quality of life diseases that occur every year trust in vaccines is currently (are the symptoms mild, severe in the , now 99% being eroded, and vaccine- or fatal), healthcare resource are in adults. Therefore, thinking preventable diseases have use, the financial cost to society about vaccination across made a comeback in countries and ability to pay. This overall the whole life course is a key A scientist working on a Malaria vaccine. that had previously managed to burden-cost is then compared opportunity, making vaccination eliminate them. Findings from between different diseases and part of the increasing emphasis Furthermore, while the the Wellcome Global Monitor populations, and results can on preventative medicine for all. very early years of vaccine 2018 (wellcome.ac.uk) suggest vary greatly. For instance, the development focused primarily that an increased understanding developed and developing world THE VACCINE on assessing the efficacy of of science behind vaccines tends can have differing priorities due DEVELOPMENT PROCESS vaccines, the emphasis has to correlate with increased in large part to their healthcare Vaccine development is a long, appropriately shifted to the confidence in vaccines, which infrastructure, sanitation and costly and complex process that benefit-risk profile of vaccines. in turn impacts decisions socioeconomic circumstances. can often take more than 10–20 There is the requirement that about vaccination. Therefore, Historically, the first years to complete. Moreover, industry and regulators not only stakeholders in vaccination are vaccines were developed vaccines, unlike other medicines, demonstrate a vaccine’s efficacy, countering vaccine hesitancy against diseases with high are not being given to people but equally its safety profile. This through education and by morbidity and mortality rates, who are already suffering from requires more investigations increasing the pool of easy-to- such as smallpox (successfully a specific illness; vaccines are throughout the development find and easy-to-comprehend, eradicated in 1980), diphtheria given to millions of healthy process, even after vaccines balanced information on and tetanus; diseases which individuals with the aim to help are licensed, along with more immunization. As a leading also primarily affected children. prevent them from contracting the comprehensive regulatory and developer of vaccines, GSK Great societal progress was disease. Therefore, it is critically licensing procedures; but all with has a part to play in this, with made because of advances in the important that vaccine developers the aim of ensuring that new experts who are well positioned fight against these diseases. In and regulators meet the highest vaccines have a positive benefit- to provide insights into the the early 1900s, families tended standards and demonstrate that risk profile – in other words that vaccines of today, and those that to be much larger (often due the benefit of any new vaccines far the benefits far outweigh any are to come. to the threat of high childhood outweigh any potential risks. potential risks.

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target age. The aim of phase I is granted by external authorities at to test the safety of the vaccine the regional (for example by the and assess the immune response European Medicines Agency in that it causes on humans. Phase Europe) and/or national level (for II trials involve a larger group of example by the Food and Drug volunteers (100–1,000), confirms Administration in the US). formulations and doses, identifies if there is a need for boosters and MANUFACTURING, TESTING determines the best intervals AND SAFETY MONITORING between each dose. This stage A little known but important again evaluates safety, immune fact about vaccines is that response and, sometimes, initial manufacturing a single dose results on efficacy. It may also of vaccine can take up to 24 include individuals belonging to months. This is mainly driven groups at higher risk of catching by the high number and level of the disease. Phase II trials are quality checks that are performed randomized, controlled and on every single batch that is involve a placebo group. produced. Up to 500+ quality During phase III trials, the tests are performed on more vaccine is tested on a much larger complicated vaccines, such Figure 1. Meningococcal serogroup B bacteria, commonly known as meningitis B. group of volunteers (1000s or as multivalent pneumococcal 10000s of individuals). These vaccines, before release. In THE EXPLORATORY AND body (Fig. 1). To overcome this tests are randomized, double addition, vaccine manufacturers PRE-CLINICAL STAGES roadblock, scientists under the blind and involve placebos (saline, are regularly inspected by The first step of vaccine lead of Rino Rappuoli invented a vaccine for another disease, or regulatory authorities from development is the exploratory reverse vaccinology, a process another substance). Phase III is around the world. At GSK for stage. This takes place in the lab, that screens an entire genome an important step for identifying example, at least one site in its typically takes two to four years, and uses bioinformatic tools to the less frequent possible adverse global manufacturing network and aims to identify natural or identify different genes as antigen events because these might not undergoes a routine inspection synthetic antigens that might candidates (Rappuoli, R. Vaccine show up in the much smaller by a regulatory authority almost help prevent or treat a disease. 19, 2688–2691; 2001). These are phase I and II trials. Regulatory every week, in addition to its own Historically, these antigens have then further filtered for attributes approval is sought before each internal inspection processes included virus-like particles, that would potentially make safe phase of the clinical trials, with (GSK Annual Report 2016, p. 33; weakened viruses or bacteria, and effective vaccine targets. independent boards assessing www.gsk.com). weakened bacterial toxins, or Once the antigen is identified, the safety and efficacy of the other components derived from the preclinical stage starts. vaccine candidate to help ensure The vaccine production process pathogens; and this stage has This increasingly involves using the safety of trial participants itself can be divided into the involved a lot of time-consuming cell-culture systems (relying throughout the process. following steps, with quality trial and error. Today, scientific less and less on animal testing) While phase III trials are checks happening throughout: advances, and new technologies to assess both the safety of the running, work also begins such as digitalization and artificial candidate vaccine as well as the on setting up the vaccine 1. Generating the antigen; intelligence, are helping reduce immune response it causes before manufacturing facility because by growing and harvesting the time needed to identify testing in humans is considered. it can take at least six years the pathogen’s proteins, candidate vaccines and are The journey for many candidate from the time the building polysaccharide or providing solutions for vaccines vaccines ends at this stage, but commences to the time that deoxyribonucleic acid. that were difficult to develop in those that do show promise are the facility typically gets its 2. Releasing and isolating the the past. then approved for testing on first regulatory approval. This antigen; by separating it from For example, in the case of humans. is done to ensure a seamless the media on which they are meningococcal meningitis B start in the manufacturing and grown and isolating it from (MenB), a rare but life-threatening CLINICAL TESTING supply of a new vaccine after other proteins or growth illness, the exploratory stage Phase I vaccine trials involve a licensure. The construction work mediums still present. was especially hard due to the small group of healthy volunteers and clinical trials mean that 3. Purifying the antigen; by using variability of the surface proteins (<100), although if the vaccine the company is making large different techniques according of MenB and the similarity is for children, researchers will investments, at its own financial to protein size, physico- between the MenB capsule start with adults and gradually risk, before the phase III results chemical properties, binding and other cells in the human step down to individuals at the are published and licensure is affinity or biological activity.

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4. Adding supporting pathogen interactions. Scientists costs and develop vaccine new and innovative ways to components; i.e. adjuvants today better understand how against diseases or for patient solve problems, to work better (to enhance the vaccine the human immune system populations that were previously and faster, and to maintain the recipient’s immune response), interacts with the diseases not possible. All while ensuring highest standards of quality stabilizers (to prolong shelf that infect them and are using that the highest safety and and safety. GSK recognizes life) or preservatives (to allow this knowledge, combined quality standards are maintained. that research and development for the safe use of multi-dose with the use of game-changing These technologies include (R&D) solutions may come from vials). technologies, to address new GSK’s self-amplifying mRNA many sources and welcomes 5. Filling syringes or vials; and disease areas (such as parasites) (SAM), a technology that partnerships, which range from packaging the vaccines and populations (such as older could allow our own cells to early research to late-stage before they are labelled and adults), with faster response ‘manufacture’ the antigen in-situ, development, that help to distributed worldwide. rates and shorter lead times. instead of introducing antigens advance the frontiers of disease GSK and its partners are at the into the body; bioconjugate prevention. More than 90% of To support post-licensure forefront of this new wave of technology, which could remove GSK’s vaccines are developed vaccine safety surveillance and science and technology. They complexity from production in partnership and the company pharmacovigilance, vaccine are opening new possibilities of conjugate vaccines; and has more than 150 active companies such as GSK employ for global health initiatives that adjuvants. scientific collaborations with a dedicated team who, through aim to reduce the burden of Adjuvants are substances pharma and biotech companies, regular engagement activities diseases such as malaria and designed to enhance our consortia, charities, foundations, with regulatory authorities tuberculosis, and new ways to immune response to vaccines. government researchers, and/or independent external tackle anti-microbial resistance. Although adjuvants have been academic groups and businesses experts, continually evaluate These new discoveries are also used in vaccines since the in non-life sciences. GSK also the benefit-risk profile of GSK starting to unleash the potential 1930s, scientists today have a provides opportunities for PhD vaccines throughout their of therapeutic vaccines for better understanding of how or postdoctoral researchers to entire lifecycle. Their work diseases like chronic obstructive the human immune system work on cross-disciplinary R&D typically includes long-term pulmonary disease (COPD). interacts with the pathogens projects for the discovery and effectiveness and safety studies, COPD affects around 10% of it confronts; including the part early development of vaccines. studies on broader populations the population >40 years of age played by adjuvants in producing and ongoing characterization and is the third most common and controlling an immune FROM VACCINES TO and quantification of potential cause of death worldwide, with a response. For example, as we VACCINATION safety signals. Routine global death toll of 3.1 million in age, our immune system reduces The scientific progress being safety oversight processes, 2015. Prevalence of the disease is its ability to mount an effective achieved, and solutions established by the authorities increasing and millions affected response to . This developed, will only benefit for medicinal products, include by the disease do not even know also means that our immune individuals and society if the independent assessment of that they have it. Therefore, system has lower ability to vaccines are used and turned available safety data by experts GSK is currently developing a mount an effective response to into vaccination. In addition to in regulatory authorities and vaccine targeting the bacteria most vaccinations. Therefore, developing and manufacturing public health institutes and aim implicated in 30–45% of acute a new generation of adjuvanted cutting-edge vaccines, GSK is to ensure the early detection exacerbations of COPD; non- vaccines is being designed to committed to the role it plays, and assessment of any potential typeable appropriately stimulate the together with stakeholders safety signals. Both GSK and (NTHi) and Moraxella catarrhalis immune system and thereby worldwide, in helping build independent experts also (Mcat). The aim of the COPD target diseases that primarily understanding of and confidence continue to perform studies vaccine will not be to help effect older adults, such as in vaccination by providing clear on how vaccination benefits prevent the disease itself, but shingles, COPD and RSV answers to the questions being individuals and society. This rather to reduce exacerbations, (respiratory syncytial virus), as asked. For example, parents includes, but is not limited to, slow the disease progress and well as vaccines for major global want the best for their children studies into the downstream hopefully improve the quality of health issues including malaria and may have questions about effects of vaccines, cross- life for the growing number of and tuberculosis. the effects of a vaccine on their protection and broader health people suffering and dying from child. After all, the ultimate economic aspects. COPD worldwide. PARTNERING FOR aim of the scientific progress INNOVATION being made in the development DISEASE PREVENTION A NEW ERA OF VACCINES In addition to technological of vaccines is to realize the AND THERAPY New technologies enable the advances, the key drivers of outstanding benefits that these Vaccines are the product of the industry to potentially complete scientific progress are people vaccines could potentially deliver steady and detailed progress in tests in less time, streamline – scientists, doctors and other – for our societies, and for each our understanding of human– production processes, lower experts – collaborating to find one of us.

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