Development and technology transfer of Haemophilus influenzae type b conjugate vaccines for developing countries

This paper describes the development of a Haemophilus influenzae type b (Hib) conjugate vaccine at the National Institute for Public Health and the Environment/Netherlands Vaccine Institute (RIVM/NVI, Bilthoven, The Netherlands), and the subsequent transfer of its production process to manufacturers in developing countries. In 1998, at the outset of the project, the majority of the world's children were not immunized against Hib because of the high price and limited supply of the conjugate vaccines, due partly to the fact that local manufacturers in developing countries did not master the Hib conjugate production technology. To address this problem, the RIVM/NVI has developed a robust Hib conjugate vaccine production process based on a proven model, and transferred this technology to several partners in India, Indonesia, Korea and China. As a result, emerging manufacturers in developing countries acquired modern technologies previously unavailable to them. This has in turn facilitated their approach to producing other conjugate vaccines. As an additional spin-off from the project, a World Health Organization (WHO) Hib quality control (QC) course was designed and conducted at the RIVM/NVI, resulting in an increased regulatory capacity for conjugate vaccines in developing countries at the National Regulatory Authority (NRA) level. For the local populations, this has translated into an increased and sustainable supply of affordable Hib conjugate-containing combination vaccines. During the course of this project, developing countries have demonstrated their ability to produce large quantities of high-quality modern vaccines after a successful transfer of the technology.     

Sustainable vaccine manufacturing in low- and middle-Income countries

The sustainable manufacturing of vaccines in developing countries is critical to increasing equitable access to vaccines and pandemic preparedness globally. Sustainable manufacturing requires that organizations engaged in the development, production and supply of vaccines have viable business models and incentives to manufacture vaccine products.The expanding manufacturing capabilities and capacities of developing countries vaccine manufacturers (DCVMs) are increasingly positioning these organizations to meet the national and regional public health needs in developing countries; however, key industry challenges such as regulatory barriers, low prices and demand uncertainty for vaccine products, and limited R&D funding threaten the long-term viability of vaccine manufacturers.This study assesses the technical capabilities, manufacturing capacities, and aspirational plans of DCVMs, exemplifying the business models and strategies undertaken to sustainably manufacture vaccines in developing countries. The public health importance of a healthy vaccine industry which enables manufacturers is discussed throughout.Vaccine manufacturers reported diverse product portfolios and R&D pipelines and utilized an array of vaccine technology platforms. Large manufacturing capacities were reported, a critical factor in manufacturers achieving economies of scale and supplying large volumes of vaccine doses to the world’s most populous regions. Partnerships and collaboration within the industry and with international organizations along the vaccine value-chain were cited with high frequency. Manufacturers also reported aspirational plans to enter new markets, acquire new technologies and invest in the development of novel and improved vaccines.As DCVMs aim to have an increasing impact on the global vaccine ecosystem, a coordinated multi-stakeholder approach is required alleviate critical industry barriers to ensure that all efforts produce vaccines are sustainable and enable developing countries to realize the public health benefit of vaccines.     

An international technology platform for influenza vaccines

Since 2008, the World Health Organization has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or improve their pandemic influenza vaccine production capacity. To facilitate this ambitious project, an influenza vaccine technology platform (or "hub") was established at the Netherlands Vaccine Institute for training and technology transfer to developing countries. During its first two years of operation, a robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production was established under international Good Manufacturing Practice standards, as well as in-process and release assays. A course curriculum was designed, including a two-volume practical handbook on production and quality control. Four generic hands-on training courses were successfully realized for over 40 employees from 15 developing country manufacturers. Planned extensions to the curriculum include cell-culture based technology for viral vaccine production, split virion influenza production, and generic adjuvant formulation. We conclude that technology transfer through the hub model works well, significantly builds vaccine manufacturing capacity in developing countries, and thereby increases global and equitable access to vaccines of high public health relevance.     

A strategic vaccine facility for the UK

This paper describes a proposed Strategic Vaccine Facility (SVF) to provide a capability to the UK to deal with new and emerging disease threats. It would underpin the vaccine manufacturing industry by developing expertise and technology to enable rapid manufacture of small batches of vaccines for emergency use against agents, such as bioterrorist agents and emerging diseases. It would have a rare ability to work with dangerous pathogens under containment, allowing the production of inactivated and live vaccines, which would be difficult in a conventional plant. The facility's output will include vaccine candidates and manufacturing protocols for transfer to industry, small vaccine batches for emergency use or clinical trials, and vaccine reference standards. It would also be available for manufacturing small batches of experimental and public health vaccines for the UK and the developing world, allowing clinical trials to be undertaken against key diseases.     

Quality vaccines for all people: Report on the 16th annual general meeting of the Developing Countries Vaccine Manufacturers' Network, 05–07th October 2015, Bangkok,Thailand

The Developing Countries Vaccine Manufacturers Network (DCVMN) assembled high-profile leaders from global health organisations and vaccine manufactures for its 16th Annual General Meeting to work towards a common goal: providing quality vaccines for all people.Vaccines contribute to a healthy community and robust health system; the Ebola outbreak has raised awareness of the threat and damage one single infectious disease can make, and it is clear that the world was not prepared. However, more research to better understand emerging infectious agents might lead to suitable vaccines which help prevent future outbreaks.DCVMN members presented their progress in developing novel vaccines against Dengue, HPV, Chikungunya, Cholera, cell-based influenza and other vaccines, demonstrating the commitment towards eliminating and eradicating preventable diseases worldwide through global collaboration and technology transfer. The successful introduction of novel Sabin-IPV and Oral Cholera vaccine in China and Korea respectively in 2015 was highlighted.In order to achieve global immunisation, local authorities and community leaders play an important role in the decision-making in vaccine introduction and uptake, based on the ability of vaccines to protect vaccinated people and protect non-vaccinated in the community through herd immunity. Reducing the risk of vaccine shortages can also be achieved by increasing regulatory convergence at regional and international levels. Combatting preventable diseases remains challenging, and collective efforts for improving multi-centre clinical trials, creating regional vaccine security strategies, fostering developing vaccine markets and procurement, and building trust in vaccines were discussed.     

The Developing Countries Vaccine Manufacturers' Network (DCVMN) is a critical constituency to ensure access to vaccines in developing countries

Six years after its establishment, the Developing Countries Vaccine Manufacturers' Network (DCVMN) has become the main representing body for emerging vaccine manufacturers from the developing world. The Network's main strategic priority (increase access to DPT-based combination vaccines containing vaccines against Hepatitis B (HepB) and Haemophilus influenzae type b (Hib)) has now come close to fulfillment due in part to the transfer of conjugation technology from The Netherlands Vaccine Institute (NVI) to various manufacturers of the Network. It is argued that at the international level more push mechanisms for product development involving DCVM are needed, including those promoting access to technology and transfer of technology, know how and technical skills from Organization for Economic Co-operation and Development (OECD) countries to developing countries. At the national level, governments of countries in which DCVMN manufacturers operate should provide more generous funding for all aspects of vaccines and immunization including incentives to manufacturers to develop and import new technologies. These two approaches will contribute to the long-term viability of domestic or regional vaccine manufacturing, which in itself is critical to ensure global equity of access to vaccines.     

Lessons learned during the development and transfer of technology related to a new Hib conjugate vaccine to emerging vaccine manufacturers

The incidence of Haemophilus Influenzae type b (Hib) disease in developed countries has decreased since the introduction of Hib conjugate vaccines in their National Immunization Programs (NIP). In countries where Hib vaccination is not applied routinely, due to limited availability and high cost of the vaccines, invasive Hib disease is still a cause of mortality. Through the development of a production process for a Hib conjugate vaccine and related quality control tests and the transfer of this technology to emerging vaccine manufacturers in developing countries, a substantial contribution was made to the availability and affordability of Hib conjugate vaccines in these countries. Technology transfer is considered to be one of the fastest ways to get access to the technology needed for the production of vaccines. The first Hib conjugate vaccine based on the transferred technology was licensed in 2007, since then more Hib vaccines based on this technology were licensed.     

WHO expectation and industry goals

It is expected the world's vaccine market will show a robust growth over the next few years, yet this growth will predominantly come from introduction of new vaccines in industrialised countries. Economic market forces will increasingly direct vaccine sales and vaccine development towards the needs of markets with effective purchasing power. Yet the scientific and technological progress that drives the development of such innovative vaccines holds the promise of applicability for vaccines that are highly desirable for developing countries. Corrective measures that take into account economic and industrial reality must be considered to span the widening gap between richer and poorer countries in terms of availability and general use of current and recent vaccines. Such measures must help developing countries to get access to future vaccines for diseases that predominantly or exclusively affect them, but for which the poor economic prospects do not provide a basis for the vaccine industry to undertake costly research and development programmes. Recent initiatives such as GAVI, including the establishment of a reliable, guaranteed purchase fund, could provide a solution to the problem.     

Vaccines: New challenges,new paradigms,new opportunities: Report of the 22nd DCVMN Annual General Meeting

The Developing Countries Vaccine Manufacturers Network held its 22nd Annual General Meeting in October 2021. Vaccine manufacturing experts, leaders from global public health organizations and dignitaries from governments and multilateral organizations discussed the challenges and opportunities emerging from the COVID-19 pandemic. Over 350 delegates from 33 countries, representing over 70 organizations partook in the meetings deliberations.The development and scaled-up production of several safe and effective vaccines against COVID-19 resulted in over 12 billion doses being produced by the end of 2021. Unfortunately, this scientific achievement and outstanding industry effort has been overshadowed by the striking inequity in access to COVID-19 vaccines. High and upper middle-income countries have received 75% of the vaccines, while in Africa, less than 5% of the people are fully vaccinated. The inequitable access to vaccines is an issue of national health security, which has stressed the need to establish local vaccine manufacturing capacity in Africa. Key partnerships, initiatives and the deliberate strategies required to achieve sustainable manufacturing on the continent were discussed. The ability to acquire technology, access markets and financing mechanisms, and workforce development were reported as key enablers to achieving a healthy ecosystem.Innovative vaccine technologies, new regulatory approaches, and the importance of voluntary technology transfers in increasing the global supply capacity of both COVID-19 vaccines and traditional vaccines were highlighted. In reviewing the lessons learned from the pandemic, speakers shared a consensus that innovation and partnerships will be central to any solution proposed to mitigate the current pandemic and prepare for future ones.     

Financial requirements of immunisation programmes in developing countries: a 2004-2014 perspective

Vaccines are a key contributor to public health, especially in developing countries. Despite numerous demonstrations of the cost-effectiveness of immunisation, vaccines spending accounted for only 1.7% of the total pharmaceutical market in 2002, when UNICEF estimated that 34 million children were not reached by routine immunisation, most of them in developing countries. Several international organizations or initiatives, like the Global Alliance for Vaccines and Immunisation (GAVI), have defined a long-term goal of universal immunisation in developing countries. There is an urgent need to estimate the financial resources required to meet this goal. The objective of this study was to anticipate the funding needs for childhood immunisation in developing countries over the 2004-2014 period. The study scope includes all the 75 countries eligible for support from GAVI, and covers existing vaccines that are considered as a priority for GAVI (DTP (diphtheria, tetanus, pertussis), hepatitis B, Haemophilus influenzae type b (as a stand alone presentation or in combination with DTP) and yellow fever) as well as future vaccines (meningitis A and C, rotavirus, human papilloma virus (HPV), malaria, Streptococcus pneumoniae and tuberculosis) likely to be available within the 10-year period. We developed a methodology to estimate the number of doses required, based on disease prevalence and incidence, target populations, introduction dates of new vaccines, coverage dynamics and dosing regimen. The introduction price and price evolution of vaccines over time were modelled, taking into account the type of vaccine, the expected return on investment from vaccine manufacturers and the competitive landscape. Non-vaccine costs (capital costs and non-vaccine recurrent costs) were estimated based on the number of people immunised and number of doses dispensed, using available case studies as a reference. According to the optimal scenario that would consider the provision of all vaccines to all relevant developing countries as soon as they are available, funding requirements to cover the associated total costs over the 10-year period were estimated to be about US$ 30 billion. Vaccines-related costs represent the largest share, with estimated costs of US$ 21 billion (among which 18 billion for new vaccines), the remaining needs being split between capital costs and other recurrent costs. Accounting for the main imponderables (such as delay in vaccines launch compared to industry plans) as well as probable phasing of vaccine introduction in countries, the total costs of immunisation would be reduced to US$ 14-17 billion over the same period. Vaccines-related costs represent the largest share (US$ 7.1-9.3 billion, among which 4.3-6.5 billion for new vaccines). This study advocates for the anticipation of the substantial financial resources needed to (a) purchase and introduce these vaccines in the developing countries in order to reduce the time lag between availability in industrialised and developing countries; and (b) stimulate vaccine researchers and manufacturers to continue research and development of much needed vaccines for the developing world.     

Impact of BRICS’ investment in vaccine development on the global vaccine market

Brazil, the Russian Federation, India, China and South Africa – the countries known as BRICS – have made considerable progress in vaccine production, regulation and development over the past 20 years. In 1993, all five countries were producing vaccines but the processes used were outdated and non-standardized, there was little relevant research and there was negligible international recognition of the products. By 2014, all five countries had strong initiatives for the development of vaccine technology and had greatly improved their national regulatory capacity. South Africa was then the only BRICS country that was not completely producing vaccines. South Africa is now in the process of re-establishing its own vaccine production and passing beyond the stage of simply importing, formulating and filling vaccine bulks. Changes in the public sector’s price per dose of selected vaccines, the global market share represented by products from specific manufacturers, and the attractiveness, for multinational companies, of partnership and investment opportunities in BRICS companies have all been analysed. The results indicate that the BRICS countries have had a major impact on vaccine price and availability, with much of that impact attributable to the output of Indian vaccine manufacturers. China is expected to have a greater impact soon, given the anticipated development of Chinese vaccine manufacturers in the near future. BRICS’ accomplishments in the field of vaccine development are expected to reshape the global vaccine market and accelerate access to vaccines in the developing world. The challenge is to turn these expectations into strategic actions and practical outcomes.     

Global challenges of implementing human papillomavirus vaccines

Human Papillomavirus vaccines are widely hailed as a sweeping pharmaceutical innovation for the universal benefit of all women. The implementation of the vaccines, however, is far from universal or equitable. Socio-economically marginalized women in emerging and developing, and many advanced economies alike, suffer a disproportionately large burden of cervical cancer. Despite the marketing of Human Papillomavirus vaccines as the solution to cervical cancer, the market authorization (licensing) of the vaccines has not translated into universal equitable access. Vaccine implementation for vulnerable girls and women faces multiple barriers that include high vaccine costs, inadequate delivery infrastructure, and lack of community engagement to generate awareness about cervical cancer and early screening tools. For Human Papillomavirus vaccines to work as a public health solution, the quality-assured delivery of cheaper vaccines must be integrated with strengthened capacity for community-based health education and screening.     

Chapter 15: HPV vaccine use in the developing world

Human papillomavirus (HPV)-related morbidity and mortality from cervical cancer primarily occurs in the developing world, where, unfortunately, access to vaccines in general, and expensive newer vaccines in particular, is often more limited than in the industrialized world. In addition, secondary prevention methods such as HPV screening, Pap testing, or visual inspection are uncommon in the developing world. The HPV vaccine will be first introduced into the industrialized countries and it will then, over the course of time, become used in the developing countries. HPV vaccine should be introduced in the framework of comprehensive cervical cancer control, and offers an opportunity to bring together a wide range of constituents who have not to date worked closely on vaccination. Ultimately, the decision of whether and when a vaccine will be introduced will depend on individual countries. To prepare for decisions on HPV vaccine use, the sexual and reproductive health (SRH; including adolescent health), immunization, and cancer control communities need to work together to analyze the appropriate data and build international and national consensus. The timeframe for other newer vaccines, such as hepatitis B and Hib, has been measured in decades, and the challenge to the public sector is to greatly shorten the time needed to make HPV vaccines available and affordable for the developing world, where their impact will be greatest.     

Public health requirements for rapid progress in global health

Abstract

Effective public health interventions can save hundreds of millions of lives in developing countries, as well as create broad social and economic benefits. Unfortunately, public health approaches and solutions applied in developed countries are often assumed to be inappropriate or unattainable in developing countries. This has sometimes forestalled effective interventions in parts of the world where they are most needed, despite conditions that now facilitate lasting solutions to both long-standing and emerging global public health problems. Core public health functions are similar regardless of a country's income level. Although some resource-intensive approaches from industrialised nations are inappropriate in less developed countries, many basic public health measures achieved decades ago in developed countries are urgently needed, highly appropriate, extremely cost-effective and eminently attainable in developing countries today. About half of the disease burden in low and middle-income countries is now from non-communicable diseases, but non-communicable disease epidemics that will otherwise increase rapidly in the developing world can be avoided or reversed. Progress of public health in developing countries is possible, but will require sufficient funding and human resources; improved physical plant and information systems; effective programme implementation and regulatory capacity; and, most importantly, political will at the highest levels of government.     

Vaccines,inspiring innovation in health

This report covers the topics of pandemics, epidemics and partnerships, including regulatory convergence initiatives, new technologies and novel vaccines, discussed by leading public and private sector stakeholders at the 18th Annual General Meeting (AGM) of the Developing Countries Vaccine Manufacturers’ Network (DCVMN). Contributions of Gavi and the vaccine industry from emerging countries to the growing global vaccine market, by improving the supply base from manufacturers in developing countries and contributing to 58% of doses, were highlighted. The Coalition for Epidemic Preparedness Innovations (CEPI), the International Vaccine Institute (IVI) and others reported on new strategies to ensure speedy progress in preclinical and clinical development of innovative vaccines for future MERS, Zika or other outbreak response. Priorities for vaccine stockpiling, to assure readiness during emergencies and to prevent outbreaks due to re-emerging diseases such as yellow fever, cholera and poliomyelitis, were outlined. The role of partnerships in improving global vaccine access, procurement and immunization coverage, and shared concerns were reviewed. The World Health Organization (WHO) and other international collaborating partners provided updates on the Product, Price and Procurement database, the prequalification of vaccines, the control of neglected tropical diseases, particularly the new rabies elimination initiative, and regulatory convergence proposals to accelerate vaccine registration in developing countries. Updates on supply chain innovations and novel vaccine platforms were presented. The discussions enabled members and partners to reflect on efficiency of research & development, supply chain tools and trends in packaging technologies improving delivery of existing vaccines, and allowing a deeper understanding of the current public-health objectives, industry financing, and global policies, required to ensure optimal investments, alignment and stability of vaccine supply in developing countries.     

Influenza vaccine production for Brazil: a classic example of successful North-South bilateral technology transfer

Technology transfer is a promising approach to increase vaccine production at an affordable price in developing countries. In the case of influenza, it is imperative that developing countries acquire the technology to produce pandemic vaccines through the transfer of know-how, as this will be the only way for the majority of these countries to face the huge demand for vaccine created by influenza pandemics. Access to domestically produced influenza vaccine in such health crises is thus an important national defence strategy. However, technology transfer is not a simple undertaking. It requires a committed provider who is willing to transfer a complete production process, and not just the formulation and fill-finish parts of the process. It requires a recipient with established experience in vaccine production for human use and the ability to conduct research into new developments. In addition, the country of the recipient should preferably have sufficient financial resources to support the undertaking, and an internal market for the new vaccine. Technology transfer should create a solid partnership that results in the joint development of new competency, improvements to the product, and to further innovation. The Instituto Butantan-sanofi pasteur partnership can be seen as a model for successful technology transfer and has led to the technological independence of the Instituto Butantan in the use a strategic public health tool.     

Managing the effect of TRIPS on availability of priority vaccines

The stated purpose of intellectual property protection is to stimulate innovation. The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) requires all Members of the World Trade Organization (WTO) to enact national laws conferring minimum standards of intellectual property protection by certain deadlines. Critics of the Agreement fear that such action is inconsistent with ensuring access to medicines in the developing world. A WHO convened meeting on intellectual property rights and vaccines in developing countries, on which this paper is based, found no evidence that TRIPS has stimulated innovation in developing market vaccine development (where markets are weak) or that protection of intellectual property rights has had a negative effect on access to vaccines. However, access to future vaccines in the developing world could be threatened by compliance with TRIPS. The management of such threats requires adherence of all countries to the Doha Declaration on TRIPS, and the protections guaranteed by the Agreement itself, vigilance on TRIPS-plus elements of free trade agreements, developing frameworks for licensing and technology transfer, and promoting innovative vaccine development in developing countries. The role of international organizations in defining best practices, dissemination of information, and monitoring TRIPS impact will be crucial to ensuring optimal access to priority new vaccines for the developing world.     

The Meningitis Vaccine Project

Epidemic meningococcal meningitis is an important public health problem in sub-Saharan Africa. Current control measures rely on reactive immunizations with polysaccharide (PS) vaccines that do not induce herd immunity and are of limited effectiveness in those under 2 years of age. Conversely, polysaccharide conjugate vaccines are effective in infants and have consistently shown an important effect on decreasing carriage, two characteristics that facilitate disease control. In 2001 the Meningitis Vaccine Project (MVP) was created as a partnership between PATH and the World Health Organization (WHO) with the goal of eliminating meningococcal epidemics in Africa through the development, licensure, introduction, and widespread use of conjugate meningococcal vaccines. Since group A Neisseria meningitidis (N. meningitidis) is the dominant pathogen causing epidemic meningitis in Africa MVP is developing an affordable (US$ 0.40 per dose) meningococcal A (Men A) conjugate vaccine through an innovative international partnership that saw transfer of a conjugation and fermentation technology to a developing country vaccine manufacturer. A Phase 1 study of the vaccine in India has shown that the product is safe and immunogenic. Phase 2 studies have begun in Africa, and a large demonstration study of the conjugate vaccine is envisioned for 2008-2009. After extensive consultations with African public health officials a vaccine introduction plan has been developed that includes introduction of the Men A conjugate vaccine into standard Expanded Programme on Immunization (EPI) schedules but also emphasizes mass vaccination of 1-29 years old to induce herd immunity, a strategy that has been shown to be highly effective when the meningococcal C (Men C) conjugate vaccine was introduced in several European countries. The MVP model is a clear example of the usefulness of a "push mechanism" to finance the development of a needed vaccine for the developing world.     

Advancing new vaccines against pandemic influenza in low-resource countries

With the support of the Biomedical Advanced Research and Development Authority (BARDA), PATH is working with governments and vaccine manufacturers to strengthen their influenza vaccine manufacturing capacity and improve their ability to respond to emerging pandemic influenza viruses. Vaccines directed against influenza A/H5N1 and A/H7N9 strains are a particular focus, given the potential for these viruses to acquire properties that may lead to a pandemic. This paper will review influenza vaccine development from a developing country perspective and PATH's support of this effort. Several vaccines are currently in preclinical and clinical development at our partners for seasonal and pandemic influenza in Vietnam (IVAC and VABIOTECH), Serbia (Torlak), China (BCHT), Brazil (Butantan), and India (SII). Products in development include split, whole-virus inactivated and live attenuated influenza vaccines (LAIVs). Additionally, while most manufacturers propagate the virus in eggs, PATH is supporting the development of cell-based processes that could substantially increase global manufacturing capacity and flexibility. We review recent data from clinical trials of pandemic influenza vaccines manufactured in developing countries. An important discussion is on the role of whole virion vaccines for H5N1, given the poor immunogenicity of split vaccines and the complexity involved in developing potent adjuvants.     

The introduction of new vaccines into developing countries. III. The role of intellectual property

The development of new vaccines that address the particular needs of developing countries has been proceeding slowly. A number of new public sector vaccine research and development initiatives have been launched to address this problem. These new initiatives find that they often wish to collaborate with the private sector and, in collaborating with the private sector, they must address issues of intellectual property (IP) management. It has not been well understood why IP management is important and how such management by public sector groups can best be conducted. IP management has become very important because vaccine research and development is driven by the regulatory process. The regulatory process has increased the cost of vaccine development to very high levels especially for the highly sophisticated new vaccines currently under development. Thus, investors seek IP protection for the required large investments. Conversely, we assert this concept as a new insight, IP rights are essential for mobilizing the significant funds necessary to meet regulatory requirements. Thus, IP rights are of value not only for investors but also for the public at large. In the absence of public sector mechanisms to carry out the functions that the private sector currently conducts, the public sector needs to increase its sophistication in IP management and needs to identify and implement strategies that will help the public sector to achieve its public health goals, especially for the poor and, among these individuals, the poor in developing countries. This paper suggests some strategies that might be used by the public sector to help achieve its public health goals, especially for the poor.