Next generation vaccines

In February this year, about 100 delegates gathered for three days in Vienna (Austria) for the Next Generation Vaccines conference. The meeting held in the Vienna Hilton Hotel from 23rd–25th February 2011 had a strong focus on biotech and industry. The conference organizer Jacob Fleming managed to put together a versatile program ranging from the future generation of vaccines to manufacturing, vaccine distribution and delivery, to regulatory and public health issues. Carefully selected top industry experts presented first-hand experience and shared solutions for overcoming the latest challenges in the field of vaccinology. The program also included several case study presentations on novel vaccine candidates in different stages of development. An interactive pre-conference workshop as well as interactive panel discussions during the meeting allowed all delegates to gain new knowledge and become involved in lively discussions on timely, interesting and sometimes controversial topics related to vaccines.

in February this year, about 100 delegates gathered for three days in vienna (Austria) for the Next Generation vaccines conference. The meeting held in the vienna Hilton Hotel from 23rd-25th February 2011 had a strong focus on biotech and industry. The conference organizer Jacob Fleming managed to put together a versatile program ranging from the future generation of vaccines to manufacturing, vaccine distribution and delivery, to regulatory and public health issues. Carefully selected top industry experts presented first-hand experience and shared solutions for overcoming the latest challenges in the field of vaccinology. The program also included several case study presentations on novel vaccine candidates in different stages of development. An interactive pre-conference workshop as well as interactive panel discussions during the meeting allowed all delegates to gain new knowledge and become involved in lively discussions on timely, interesting and sometimes controversial topics related to vaccines.
against polio or Hib meningitis demonstrate the great potential of vaccination. The potentially huge vaccine market is dominated by a few major pharma companies, but it is no secret that innovation-such as new antigens, adjuvants and vectors, as well as novel ways of administration and production-is often driven by new vaccine players. There is still a long list of infectious disease agents for which no vaccines exist, and the ones that are left to develop are of course the more complicated ones. While scientific and technological progress drive vaccine innovation, the development of new vaccines is hindered by complex manufacturing processes and quality measures, extremely low acceptable levels of side-effects, a difficult registration pathway, and sometimesdwindling vaccine acceptance. The key challenges faced by vaccine companies can be summarized as availability, affordability and sustainability. In particular, this means making all vaccines available whenever possible to all countries as early as possible, in sufficient quality and quantity to meet global demand (availability), setting vaccine prices at levels that allow all countries not only the developed world to purchase the product (affordability), building a successful business by supplying high-quality vaccines to all who need them, and securing sustained investment in R&D for the development of novel vaccines as well as maintenance and continuity in upgrading manufacturing facilities (sustainability). Dr. Zettlmeissl ended his presentation with a few selected vaccine candidates from Intercell's pipeline. Control of hospitalacquired infections (HAI) is a great challenge and holds great market opportunities. To this end, Intercell is involved in the development of vaccines against Staphylococcus aureus (Phase II/ III), Pseudomonas aeruginosa (Phase II) and Clostridium difficile (Phase I). Their therapeutic vaccine against Hepatitis C (Phase I/II) shows a good safety profile and a statistically significant 6 months viral-load reduction.
Another therapeutic vaccine-ProCervix-was discussed by Dr. Benedikt Timmerman (Genticel, France). He emphasized that the eradication of cervical cancer will require a coupled approach of preventative and therapeutic vaccines. Genticel's therapeutic human papilloma virus (HPV) vaccine might be a solution for nearly 100 million women carrying HPV16 and/ or HPV18. ProCervix is based on the company's proprietary Adenylate Cyclase (CyaA) antigen delivery platform. CyaA is designed by nature to target antigen presenting cells (APCs) and can effectively deliver HPV epitopes to both CD4 + and CD8 + cells. The vaccine consists of 2 recombinant E. coli-derived CyaA proteins (each containing HPV-E7). After preclinical results satisfied manufacturing, pharmacology and safety requirements, ProCervix entered a Phase I trial in July 2010. Objectives of the ©2 0 1 1 L a n d e s B i o s c i e n c e . D o n o t d i s t r i b u t e .
www.landesbioscience.com Human vaccines 719 review MeeTiNG reporT trial are to determine general safety and local tolerance upon intradermal administration as well as immunogenicity. The results are expected towards the end of 2011. The potential of therapeutic vaccines based on virus-like particles (VLP's) was discussed by Dr. Martin Bachmann (Cytos Biotechnology AG, Switzerland). He presented two of the company's products under development, a Type 2 Diabetes (T2D) vaccine (CYT013-IL1bQb) and an immunomodulator for Asthma (CYT003-QbG10). In the case of the T2D vaccine, interleukin-1b (IL-1b), previously identified as a key mediator of this metabolic disorder, is displayed on VLP's. The presentation of antigens in ordered repetitive antigen arrays (i.e., VLP's) enables successful immunization against self-molecules. A specific antibody response against IL-1b was elicited in animals immunized with the T2D vaccine candidate. The vaccine is being tested in a small Phase I clinical trial, looking at safety, tolerability, immunogenicity and dosing. A new biologics product for asthma and allergies (CYT003-QbG10) uses VLP's to deliver a normally unstable A-type CpG DNA, a known ligand for Tolllike receptor 9 (TLR9). Generally, TLR's are important for the activation of the innate immune system and the induction of antiallergic TH1 responses and/ or anti-inflammatory regulatory T-cells. In a recent Phase II clinical trial, this immunomodulator was tested in subjects with persistent allergic asthma requiring long-term treatment with inhaled corticosteroids (ICS). Sixtythree patients were randomized to receive placebo or 7 weekly to bi-weekly injections of the immunomodulator, while at the same time ICS therapy was stepwise reduced to induce symptoms and markers of inflammation. In the vaccinated group, significant and medically relevant improvements were observed already after two weeks, and lung function was preserved despite ICS withdrawal. Overall, the vaccinated group showed improvement of asthma control compared to placebo. The mechanism of action of this immunomodulator likely includes the induction of interferon-α (IFNα), leading to a shutdown of TH2 responses and inflammatory cytokines.

Optimizing Pre-clinical and Clinical Trials Performance
Dr. Danilo Casimiro (Merck & Co.) discussed the different stages of the fundamental process of vaccine discovery and accompanied his remarks with examples from the development of Merck's HPV vaccine Gardasil. He generally divided the vaccine discovery process into target identification and validation, lead identification and optimization, and post-discovery/development of vaccines. The criteria for selection of prioritized disease targets for vaccine R&D vary between developed and developing nations. While medical need, proof-of-concept and technical feasibility are shared by both, the availability of funding for vaccine programs and low-cost manufacturing are essential factors in developing countries. Once the disease target has been determined, antigens derived from the target infectious agents are screened for their ability to elicit a particular protective immune response and for their protective efficacy profiles in relevant animal models. Next, the route of immunization, the formulation and delivery systems are optimized. Post-discovery optimization includes the development of a scalable robust process for vaccine manufacturing and clinical development in the target population. Developing vaccines is a long and costly process, although less so than most small-molecule therapeutics. Therefore, programs should be chosen carefully, and the right selection of the immunological and efficacy biomarker to guide R&D is of great importance. The introduction of innovative technologies-like the use of new antigen selection methods, expression systems, cell lines and adjuvants-at different steps in discovery and development can cut the R&D timeline in a race to market. For example, Intercell's proprietary AIP (antigen identification program) technology was successfully used to identify the optimal antigen for a S. aureus vaccine, which is being advanced by Merck & Co.

News on Influenza
The fruitful collaboration of two leaders in their field, Sanofi Pasteur and Becton Dickinson, led to the recent launch of an intradermal (ID) influenza vaccine, Intanza/ IDflu. During the six years of development, both companies had to overcome difficult industrial challenges and constraints, as Dr. Antoine Alcaron (sanofi pasteur, France) pointed out in his presentation. The newly developed glass syringe contains a micro-needle with very high level of accuracy and a very low dead-volume (<10µl), and is relatively easy to use. The low volume used for ID immunization (0.1 mL), required the development of a very concentrated formulation and the use of new filling technologies and methods. Intanza is a non-adjuvanted trivalent inactivated splitvirion influenza vaccine. Clinical experience demonstrates that in adults, Intanza 9 µg is as immunogenic as a reference conventional intramuscular (IM) 15 µg vaccine. In the elderly, Intanza 15 µg is more immunogenic than a reference conventional IM 15 µg vaccine and equally immunogenic as a MF-59 adjuvanted IM 15 µg vaccine. Only mild adverse reactions were observed after immunization with Intanza, and the systemic safety profiles of ID and IM vaccines are comparable. Outcomes from the first vaccine acceptability study of Intanza conducted under field conditions are encouraging, with nearly all subjects being very satisfied or satisfied with the ID vaccine received, and intending to use it again for next year's flu vaccination. The reasons for satisfaction mentioned most frequently, included the minimally painful injection, the quick administration process and feeling reassured by the micro-needle. Thus, Intanza certainly has the potential to address some of the barriers and limits of standard influenza vaccination and might lead to higher coverage.
Another new generation influenza vaccine was presented by Dr. Thomas Muster (Green Hills Biotechnology, Austria). Their live-attenuated intranasal vaccine candidate DeltaFLU is made by reverse genetics. Deletions and modifications in the NS1, M1, PA, PB1, PB2 and HA genes lead to vaccine strains which are replication-deficient, highly immunogenic and grow to high titers in VERO cells. Clinical studies of seasonal (H1N1) and pandemic (H5N1) DeltaFLU vaccine in healthy adults demonstrate that the candidate vaccine is safe and immunogenic and that both local and systemic immunity is successfully induced. Seroconversion was observed in 50 and 70 percent of seronegative adults immunized with seasonal and pandemic deltaFLU, respectively. Vaccination with seasonal deltaFLU induced crossneutralizing antibodies against drift variants as well as mucosal immune responses. Dr. Muster hopes that the ease and painlessness of intranasal administration could again-like claimed for sanofi's ID vaccine-help to increase acceptance and coverage. While some experts claim that new-generation influenza vaccines like the two mentioned above have the potential to increase coverage and acceptance, Dr. Bram Palache (Abbott Biologicals B.V., Netherlands) stressed that the main problem is the insufficient implementation of existing recommendations for the prevention of influenza. There is no doubt that influenza is a serious disease. A variety of safe and effective vaccines are available, and vaccination policy guidelines and recommendations exist. Yet, coverage is still low. According to Dr. Palache, full implementation of existing recommendations needs improved communication and innovative approaches, considering both evidence-based evaluations (scientific information) as well as non-evidence-based factors (ethics, emotions, time and costs). A joint effort of public-health authorities, health-care workers and industry could improve influenza vaccination coverage rates. For example, the public-health community should launch awareness campaigns, promote vaccine uptake for health-care workers, and support educational efforts on influenza at medical schools. Health-care workers should counsel at-risk patients about vaccine safety and benefits, vaccinate themselves, and teach medical students to vaccinate against influenza as part of professional behavior. Finally, the role of industry is the adequate and timely production and distribution of seasonal influenza vaccines, the support of WHO to facilitate best possible antigenic match for seasonal and pandemic vaccines, and R&D for influenza vaccine innovations.
While the world was preparing for a pandemic of avian H5N1, a swine-derived H1N1 caused the 2009/2010 pandemic, starting in Mexico in March 2009. The pandemic H1N1 spread rapidly (over 182,000 cases in 177 countries worldwide already by June), but fortunately, the strain turned out to be rather mild and the population was partially primed by seasonal H1N1. Dr. Philip Dormitzer (Novartis Vaccines) summarized experiences and lessons learned of the 2009/2010 influenza pandemic and provided insights into Novartis Vaccines' response to the latest pandemic. Looking at the industrial reality, it took 4-5 months from first strain to first H1N1 vaccine, despite unparalleled global efforts. In order to save valuable time, the current flu response system must be modernized. Synthetic biology enables more rapid seed generation. At Novartis, for instance, a reverse genetics system was successfully tested for the production of vaccine seed viruses for use in a MDCK-based cell culture production system. And in collaboration with the Craig Venter Institute, Novartis is pursuing a synthetic vaccinology approach for seed generation, which could potentially cut 3-4 weeks off of seed generation and free companies from dependence on receiving viruses from WHO. But in order to use vaccines made with such synthetic seeds, they need to be licensed by FDA and accepted by the public. Besides seed generation, the availability of reference reagents was a rate-limiting step in 2009, and these should therefore be made more quickly or changed to non-serum-requiring release assays. Finally, changing from egg-based to cell-culture-based vaccine production has the potential for shorter lead time and higher yields. Dr. Dormitzer emphasized that having the technical capabilities is not sufficient. Rather, partnerships with publichealth agencies must be revised and regulatory pathways have to be mapped in advance to assure better preparation for the next influenza pandemic.

Tuberculosis Vaccines
The development of a leading tuberculosis (TB) vaccine candidate and ways for its accelerated introduction were presented by Dr. Adam Stoten (Oxford-Emergent Tuberculosis Consortium Ltd., UK). The current Bacille Calmette-Guerin (BCG) vaccine, first introduced in 1921, shows variable efficacy; when given at birth, it is effective against disseminated forms of the disease in infants, however it fails to protect against pulmonary disease. Improved TB vaccines are needed in order to control the disease. However, the development of a new TB vaccine is challenging due to lack of a correlate of protection, imperfect animal models, and complex clinical endpoints. Epidemiology is pivotal in identifying potential Phase III sites and efficacy trials with large numbers of subjects, and long periods of followup are required. One promising vaccine candidate is MVA85A, developed by the OETC-a joint venture between the University of Oxford and Emergent BioSolutions. This vaccine candidate contains the major target antigen 85A of Mycobacterium tuberculosis, in a Modified Vaccinia Ankara (MVA) viral vector, which is used in a BCG-MVA85A prime-boost regimen. To date, 12 trials for MVA85A have been completed and four are ongoing. Data from 1500 vaccinated individuals (including infants, children and HIV-infected subjects) show a good safety record for MVA85A. The vaccine induces sustained highly poly-functional antigen-specific CD4 + T cells, as well as antigen-specific CD8 + T cells. An ongoing infant Phase IIb efficacy study in South Africa (commenced in 2009) includes >2700 BCG-vaccinated infants, who were either boosted with MVA85A or received placebo. The study will look at safety, immunogenicity, efficacy against disease and infection, as well as immune correlates. Another Phase IIb study in HIV-infected adults is due to commence in 2011 at two sites of sub-Saharan Africa, Senegal and South Africa. This study will include 1400 subjects (BCG status not required for entry to trial), who will be randomized to receive MVA85A or placebo, the study objectives being the same as for the above described infant trial.

Vaccine Industry in India
Dr. Satish Ravetkar (Serum Institute of India, India) looked at manufacturing capacities in developing countries, with special reference to India. In recent years, Indian Biotech firms such as Shanta Biotech, Panacea, Bharat Biotech, Serum Institute of India Ltd. (SIIL), and others have expanded and scaled up manufacturing capacities to be in line with other global players. The SIIL is able to deliver a wide range of licensed products, such as BCG, DT, HepB (recombinant), Hib conjugate, and MMR. Moreover, the company is also involved in the development and manufacturing of several new innovative vaccines currently in various clinical stages (Rotavirus-Phase II; Measles aerosol-Phase III; or Meningococcal A conjugate-awaiting licensure). Strengths of the developing world biotech sector (i.e. India) include a strong pool of scientists and engineers, cost-effective manufacturing capabilities, numerous national research laboratories and universities, as well as a fast growing drug and pharmaceutical industry. In contrast, the lack of venture capital, relatively low R&D expenditure by industry, the missing link between research and commercialization, and doubts about the ability of Indian products to meet international standards of quality are typical weaknesses of the biotech sector in developing world countries. Unreliable and unpredictable markets in developing countries present the major barriers to investment in vaccine development for these countries. The situation could be improved by ensuring consistent and predictable funding for the purchase of vaccines, differential pricing and pooled procurement, as well as increasing investments in health care systems by developing countries. While a low and affordable price for vaccines is desirable, vaccine companies should still be able to make reasonable returns producing vaccines to meet global demand-which in turn enables them to develop new vaccines. Additional resources for the development of vitally needed new vaccines should not compete with funding available for the purchase and use of existing products. After all, a vaccine manufacturer's decision to invest in the development and commercialization of vaccines, although tied to scientific progress, is based largely on economics: the costs and risks of investments and the expected return on future sales. Dr. Ravetkar closed his presentation by pointing to the positive example of MenAfriVac, the Meningococcal A conjugate vaccine developed through the Meningitis Vaccine Project (MVP) and produced at the SIIL, which has become available in autumn 2010 for widespread vaccination in African countries lying in the Meningitis belt.

Global Supply Chain for Vaccines
New trends in vaccine distribution and delivery were discussed by Dr. Tharuvai Ramesh (Pfizer). Supply network and lead times, regulatory impact, cold-chain logistics and demand signals were identified as the main drivers for supply chain complexity. Complicated networks (including drug substance, drug product, packaging and distribution), long lead times associated with biological manufacturing and release, cold-chain challenge (especially in developing countries), as well as complex regulatory aspects ask for innovative and flexible approaches in the field of vaccine distribution and delivery. End-to-end planning across the supply chain as well as a robust governance process for decision-making, issue prevention, resolution and escalation are essential. Also helpful is integrated product life cycle management and value stream optimization. To this end, the tools of Lean Six Sigma may help understand and optimize the supply chain and its processes. According to Dr. Ramesh, there is significant untapped value in industry's supply chains, which is certainly worth going after.

Regulatory Background and Trends in Vaccine Funding
Three presentations were devoted to the topics of changing regulatory background and future trends of vaccine funding. In his keynote presentation, Dr. Jerald Sadoff (Crucell, Netherlands) discussed new vaccine financing and collaborating initiatives to meet global demand. Up to now, vaccine makers invested in R&D for the developed world and waited for 10 to 20 years for costs to go down and capacities to expand, before supplying the developing world with vaccines at affordable prices. These existing vaccines often do not meet developing countries' needs for formulation, storage and packaging, and are not available in enough quantities to meet large demand from developing countries, leading to supply shortages and chronic interruption of vaccination programs. Many vaccines for diseases primarily affecting poor countries are not developed at all, because of a perceived small and risky market and the limited ability of developing countries to pay for the vaccine. Potential solutions to this problem are being tried and proposed, and can roughly be divided in Push and Pull mechanisms. Push mechanism include government financing of research, philanthropic and government funding Product Development Partnerships (PDP) of directly funding Industry-the latter could be very effective, but might be difficult to appear legitimate (public perception). Advantages of Push mechanisms would be that the money is specifically targeted to the disease of interest in absence of a known market, companies are able to take risk with new technology to approach difficult problems, and vaccines are tailored for the developing world's specific needs. An example for a successful PDP Push model is the Meningitis Vaccine Project. PATH, WHO and the Serum Institute of India collaborated to develop the Meningococcal A conjugate vaccine MenAfriVac (at 40 cents/dose), which will be used for large-scale immunization in the African "Meningitis belt", where 430 million people are at risk of infection. Pull mechanisms aim to create markets, using instruments such as the Advance Market Commitment (AMC), or FDA fast track reward for licensure of vaccine for the developing world. Advantages of Pull mechanisms would be that they take advantage of the competition between players, and that payment only occurs after a vaccine is licensed-thus reducing donor's risk. The AMC, an up-front legally binding financial commitment by donors to support purchase of target vaccines for poor countries if and when they are developed, is being applied to pneumococcal conjugate vaccine. The main objectives are to bring forward the availability of effective pneumococcal vaccines by scaling up production capacity, accelerate development of second-generation vaccines that meet developing country needs, accelerate vaccine uptake, and in general to test the AMC concept. Dr. Miles Carroll (Health Protection Agency, UK) talked about the role of Public-private partnerships (PPP) in vaccine development. PPPs have the potential to improve translation of government-funded research as well as financial return of the invested money. They de-risk innovation, so that highrisk projects may be advanced, including vaccines for emerging diseases and bio-defense. Finally, the biotech sector activity in a certain region may be stimulated. The majority of government funding goes into basic research and preclinical development of vaccines. In order to ensure that new discoveries are developed and translated into real benefits for patients, supporting translational research is a priority for the UK government, according to Dr. Carroll. As a facilitator between academia/government and industry, HPA facilitates the development of future health care interventions. Among other things, the Agency manufactures its own products, including the Anthrax vaccine and Erwinase (a therapy to treat acute lymphoblastic leukaemia), enabled the Botulinum toxin commercialization program, supports Phase IIb and III trials for a vaccine for plague, develops a realistic influenza ferret model, and supports the development of new Meningococcal disease vaccines such as MenBioVax (in collaboration with ImmBio Ltd.). Over 75 percent expenditure of HPA's Vaccine R&D program is generated from external sources, like the pharmaceutical and biotech sector, MRC, EU, Gates Foundation, Wellcome Trust or WHO. Public financial support certainly influences the vaccine development agenda, in that vaccine discovery and innovation will continue to mainly be developed by the public sector and utilised by vaccine industry.
Understanding the current regulatory environment for vaccines was the topic of Dr. Ed Geuns' (Abbott Biologicals B.V., Netherlands) presentation. Regulatory approval of medicinal products, including vaccines, is based on quality, safety and efficacy. For a successful regulatory process, the regulatory strategy should be defined well in advance and aligned with development and commercial strategies. Risk-management plans should be incorporated into the regulatory strategy at an early stage of development, and vaccine makers are encouraged to engage with key regulatory agencies, seek their advice, and have and open dialogue. However, in the current environment, market access arises as a new challenge. Hurdles to market access include reimbursement, pricing, listing by payer/region, listing by hospitals and getting dispensed. Benefit/ risk assessments will increasingly be part of regulatory strategies. To ensure market access, it is therefore important for both regulatory agencies and manufacturers to think about payers' needs and to take this perspective into consideration. Data needed for successful market access may sometimes differ from those needed for the first step of approval. Dr. Geuns concluded that the scientific and regulatory landscape for vaccines is rapidly changing due to epidemiology and innovation. Regulatory guidance is driven by scientific progress, thus vaccine manufacturers and regulators must continue working together on setting the standards for approval for the benefit of public health.
During the three days, the meeting in Vienna covered a lot of ground, with topics ranging from prophylactic to therapeutic vaccines, from preclinical research to clinical trial performance, from vaccine manufacturing to distribution, and from regulatory issues to new trends in funding. The vaccine market certainly represents an increasingly attractive segment characterized by promising vaccine candidates, rising global demand and preparations for the next pandemic influenza.