Collaboration, commitment and coordination
ALTAF A. LAL
VACCINES have contributed significantly as a cost-effective and proven intervention to prevent, control, eliminate and eradicate deadly diseases. Successful immunization campaigns have eradicated small pox (in humans) and rinderpest (in cattle). India has completed a polio-free year, which is a signifiant public health accomplishment. There is enthusiasm and progress globally towards elimination of measles, rubella and neonatal tetanus in the coming decade, as well as increased coverage of routine childhood vaccines and introduction of new vaccines.
The discovery, development and delivery of effective vaccines have been supported by the Indian government (Department of Biotechnology (www.dbtindia.nic.in), the Indian Council of Medical Research/Department of Health Research and the Department of Health and Family Welfare (www.mohfw.nic.in). Some of the vaccine development and immunization efforts are receiving collaborative support from bilateral and global entities, such as the United States Department of Health and Human Service’s National Institutes of Health and Centers for Disease Control and Prevention (www.hhs.gov), Bill and Melinda Gates Foundation (www. gates foundation.org), GAVI Alliance (www. gavialliance.org), WHO (www.who. int), and UNICEF (www. unicef.org).
The Decade of Vaccines (DoV) Collaboration (www. dovcollaborations. org), an initiative by the Bill and Melinda Gates Foundation, UNICEF, WHO, GAVI Alliance and NIAID, is developing a Global Vaccine Action Plan (GVAP), which aims to outline challenges and opportunities in discovery, development, delivery, global access, public and political advocacy of vaccines and immunization programmes.
The companion articles in this issue of Seminar are likely to focus on various inter-related aspects of vaccine development and immunization needs in developing countries, with a focus on India. One common theme, however, is bound to emerge: the need for innovation throughout the ‘life cycle’ of vaccines and immunization. Innovation in technologies is needed for vaccine development. It is also needed for financing, procurement, stockpiling and delivery of vaccines.
Immunization has served those countries that have used vaccines effectively in national programmes. Many infectious diseases that once caused millions of deaths have been eliminated. A decrease of more than 95 per cent in the incidence of diseases such as diphtheria, tetanus, pertussis, measles, mumps and rubella has been documented. Vaccines against hepatitis A, hepatitis B, haemophilus influenza type b (Hib), cervical cancer, rotavirus-attributable diarrhoea and pneumococcal disease have shown remarkable protective results, with many countries now using these vaccines in national programmes.
The vaccine product pipeline is also strong. It is expected that new vaccines against dengue, leishmaniasis, malaria, tuberculosis (improved) might be available in the next decade. There are promises of technologies that would introduce to vaccines attributes of thermostability and reduced footprint (that is, small package size). These new features are desirable for developing-country vaccine needs and will help increase vaccine coverage (by elimination or decreased demand of cold chains) and decrease cost to national immunization programmes (by making affordable vaccines available to programmes).
Among the emerging economies, India enjoys a unique position in the vaccine manufacturing and immunization arena. On the one hand Indian vaccine manufacturers have earned a reputation for making affordable and effective vaccines for use in the developing world. On the other hand, there is concern that as compared to other high-growth economies, introduction of existing and new vaccines is slow in India.
Examples would help here. Brazil, which is a giant South American country, provides BCG, DT, Dap, Dew, DTwPHib, DTwPHibHep, Hep A, Hep B, Hib, influenza, IPV, OPV, MenAC, MMR, Pneumo-Conj, Pneumo-ps, rotavirus, typhoid, varicella and yellow fever vaccines through national programmes. In some cases, specific vaccines are provided for special groups, adolescents and adults (www.who.int/countries/bra/en/).
Since the early 1970s, Brazilian citizens have access to immunization programmes. The last case of polio in the country was reported in 1989. Brazil received international certification for the eradication of indigenous transmission of wild poliovirus. In addition to providing vaccines for children, Brazilian programmes provide for vaccines for adults, especially women of childbearing age and the elderly from 60 years on. Vaccination programmes in Brazil are coordinated by the National Health Surveillance Agency, which is an agency under the Ministry of Health.
Compared to Brazil, China provides a smaller number of vaccines through its national programme. The vaccines provided are: BCG, DT, DTaP, Hep A, Hep B, JapEnc, MenA, MenAC, MMR, MR and OPV (www. who.int/countries/chn/en). The national immunization programme was established in 1978. China reported 85 per cent coverage of BCG, DPT, OPV and measles vaccines by 1990.
In 2002, the hepatitis B vaccine was added to the routine immunization schedule. In 2005, the Chinese government mandated free provision of immunizations. Another noteworthy event in 2008 was expansion from five vaccines against seven infectious diseases to 11 vaccines against 12 infectious diseases.
China has faced challenges in implementing its immunization programme. Surveys in 2004 revealed coverage of four basic vaccines was below 85 per cent. Another survey conducted in 2006 in four western provinces found vaccination coverage was below 50 per cent in some counties and the hepatitis B birth dose had a below 20 per cent delivery rate.
In India, the national immunization programme provides BCG, DTwP, Hep B, JapEn and DTwPHepBHib, Measles, OPV and tetanus toxoid (TT) vaccines, some of which are provided in only parts of the country (www. who.int/countries/ind/en). The recent announcement of introduction of pentavalent (DTwPHepBHib) in additional six states will lead to many illness prevented and deaths averted. The experiences gained will be useful in the national roll-out of pentavalent vaccine. The Indian Academy of Paediatrics (IAP) report of 2009-2011 states that while vaccine coverage in the 1980s increased from 20 per cent to about 62 per cent, subsequent gains have been limited. The 2005-2006 India National Family Health Survey (NFHS-3) revealed only 43.5 per cent of children aged 12-23 months had fully received BCG, measles, three doses of DPT and polio vaccines. Five per cent had received no vaccination at all.
There is also variability in state and district level coverage. In the recent District Level Health Survey (DLHS-3; 2007-08) full immunization coverage of children varied between 30 per cent in Uttar Pradesh, 41 per cent in Bihar, 62 per cent in Orissa and 90 per cent in Goa. Vaccine coverage in Kerala, Tamil Nadu and Pondicherry was above 90 per cent.
The results of several years of intense polio surveillance and immunization programmes have shown very promising results in 2011. Only one case of polio was reported in 2011 compared to 42 cases in 2010. The important observation to note is that Uttar Pradesh has not reported a case since April 2010 and Bihar has not reported a case since September 2010. This landmark accomplishment has been possible because of technical excellence of the National Polio Surveillance Programme (NPSP), policies of the Ministry of Health and Family Welfare and political commitments at the highest levels. We now have India free from polio this year and eradication of this disease from India is within our reach. However, in order to accomplish the goal of elimination and eventual eradication of polio, continued surveillance and immunization campaigns should remain a high priority. The lessons learnt and experiences gained will be valuable in implementing national immunization programmes, such as for elimination of measles and introduction of new vaccines.
In the immunization framework, the national advisory groups provide essential inputs to policy makers and political leaders. If used properly and in a timely manner, such inputs translate into lives saved and illness averted. An analysis of reports published in Vaccines (19 April 2010) about the governance and decision making structures of national immunization programmes in several developed and developing countries revealed the importance of the following: Is the national immunization programme enforced by national mandates/laws? Does the leadership (chairmanship) of the national immunization technical advisory group reside within or outside the government? How frequently does the technical advisory group meet? Is the technical advisory group meeting open to industry and civil society members?
The global environment in vaccine development and usage is changing rapidly and India has a prominent place in several ‘game changing’ phenomena. The global resource base committed for immunization has increased mainly through the efforts of the GAVI Alliance. The proportion of government funding allocated for immunization has also increased in many countries. According to WHO immunization survey data, more than 75 per cent of the world’s 193 countries have developed multi-year immunization plans for sustainability of programmes.
The next decade offers opportunities for development of new and improved vaccines as well as uptake of vaccines in national programmes in India. There are five core components that when connected and aligned could lead to significant public health, human development and economic development accomplishments. These core components, some of which will be revisted later, are:
1. Vaccine manufacturing, including innovative indigenous research and development. For this to happen, collaborations between private sector and academia are essential. Appropriate levels of funding should be made available for these public-private collaborations. Several Indian research institutions have world-class basic and applied research programmes in vaccine development. Few examples are: Delhi University, south campus, New Delhi (TB vaccine), Indian Institute of Sciences, Banglore (HIV vaccine), International Centre for Genetics and Biotechnology, New Delhi (Dengue, malaria and HIV vaccine), National Centre for Cholera and Enteric Diseases, Kolkatta (Chorela and HIV vaccine), Tuberculosis Research Centre, Chennai (TB and HIV vaccine), YRG-CARE, Chennai (HIV vaccine). The many excellent institutions of Indian Institutes of Technology are untapped resource for development of bio-processing, conjugation chemistry, and manufacturing technolgies for biotechnology and vaccine development. These institutions, when linked and aligned with vaccine industry, have the potential to develop innovative vaccine manufacturing technolgies that can produce ‘more for less’.
2. Development of an actionable national immunization plan that is endorsed at the highest levels in the government, and which provides for funding for procurement and administration of existing vaccines for children, adolescents and adults. There are at least two components to elaborate here. First, the presence of functional and actionable national immunization plan that provides high-level directions on use of vaccines in public and private sector. Second, there should be self-reliance for procurement of routine and new vaccines (procurement and delivery costs) through appropriate allocation of funds. The returns on these investments would be significant in terms of illness prevented, lives saved, and through economic and human development benefits.
3. Development of disease burden and epidemiologic data that would be used for prioritizing vaccines to be included in national programmes. The absence of disease burden data and relevant epidemiologic data is often cited as a reason for delay in introduction of vaccines. The lack of data also does not allow estimation of cost-benefits of vaccines which is useful for policy makers. There are several medical colleges and public institutions that specialize in epidemiologic and public health sciences, and the launch of new public health institutions (www. phfi.org) would fill the void. The objective is to develop independent data through multi-centric investigations of disease surveillance that have laboratory components in order to determine genetic and immunologic charcteristics of infectious agents.
4. Development of health systems with trained personnel needed for immunization programmes. For this to happen, the well funded and staffed immunization programme has to be part of a strong national health system. The personnel for immunization should receive continuing education in order to keep connected with changes and innovations in vaccine delivery, monitoring and evaluation, stockpiling, etc.
5. Real-time dialogue with civil society to inform and answer any questions, so that the support base for the vaccination programme is broad and well-grounded. This is one of the most critical and often ignored component of immunization. When full facts on risks and benefits of immunization are made available, confusion or concern with safety of vaccines can be eliminated. We can then reach a stage when individuals and policy makers have data on safety and effectiveness of vaccine and can make informed decisions.
Indian vaccine manufacturers are major suppliers of affordable vaccines used in the expanded programme of immunization in developing countries. Several Indian vaccine manufacturers introduced the hepatitis B vaccine in India and other developing markets at significantly lower prices than western pharmaceutical companies.
The Pune-based Serum Institute of India (SII) supplies most of the measles vaccine stock to developing countries. Through a collaborative programme that included US Food and Drug Administration, PATH and other institutions and funding from the Bill and Melinda Gates Foundation, SII has produced a vaccine against invasive meningococcal disease caused by meningococcus group A (MenAfriVac) for use in the meningitis belt of Africa.
Another Hyderabad-based company, Bharat Biotech International Limited, is conducting phase III trials of an indigenous vaccine against rotavirus. This initiative, which is an example of US-India collaboration through the Vaccine Action Plan collaboration between NIH and DBT, too has received technical and funding support from PATH, the Bill and Melinda Gates Foundation, NIH, CDC, All India Institute of Medical Sciences, and the Department of Biotechnology.
Also, another Hyderabad-based vaccine manufacturer, Shantha Biotechnics Limited, has developed an affordable vaccine against cholera. This vaccine development programme was a collaborative effort with the National Institute of Cholera and Enteric Diseases, the Indian Council of Medical Research and the International Vaccine Institute in Seoul.
The above examples demonstrate the outputs of global collaborations in vaccine development and clinical trials, where technical resources of multiple institutions were and are being used in development of effective vaccines. Recent international initiatives – including those by pharmaceutical companies and research charities, such as the India-based MSD Well-come Trust Hilleman Laboratories (www. hillemanlaboratories. org), the South Korea-based International Vaccine Institute (www.ivi. org), and the Italy-based Novartis Global Health Vaccine Institute (www.ghvi.org).
So far Indian vaccine manufacturers have produced vaccines with technologies mostly developed elsewhere. While this strategy has been successful, to remain competitive, Indian vaccine manufacturers will need to initiate in-house R&D programmes needed for development of new or improved vaccines. Indigenous innovation and development of vaccines and vaccine technologies that are relevant to local needs and epidemiologic environments will position the Indian vaccine industry in the global space.
It is obvious new models of R&D are needed for continuing to build on past innovation, and for development of effective and affordable new and improved vaccines. Technologies in very early stages of development offer hope of dissolvable thin strip or powder (granule) based thermostable vaccines, vaccines that are administered using microneedle and nano-patch devices, and vaccines that would have a small package size for easy storage and transportation. Technologies that would allow vaccinations through the oral route – for vaccines that are currently administered by the parenteral route – would make administration of vaccines in all age groups easier and increase coverage. These are the exciting frontiers before us.
The changing global environment and business plans require partnerships between organizations within a country as well as organizations across borders. Collaboration between Indian and multinational vaccine manufacturers is especially important. It is this collaboration that will introduce best practices of manufacturing, quality control and global marketing practices. The outcome will be expedited development and deployment of effective and affordable vaccines for developing, emerging and commercial markets.
Astrong vaccine industry in India has to be complemented by an effective regulatory environment that is aligned with the needs of public health and of industry, as well as in consonance with international regulatory norms. It would be highly desirable for Indian regulatory agencies to seek inputs from vaccine manufacturers and academia, so that processes and systems of regulations are of the highest quality and at the same time understood by all stakeholders involved in development and delivery of vaccines, including civil society groups. An associated and important element of the regulatory environment should include requirement for conducting post-marketing surveillance for detection of any adverse events attributable to vaccines.
Indian industry has demonstrated its ability to produce vaccines, many of which have been approved by WHO. Going forward, the expectations include: (i) place highest level of focus on product safety; (ii) establish partnerships with academia for conducting basic and clinical research needed for enhanced understanding of the biology of infection, pathogenesis and epidemiology of disease; (iii) develop capacity for research and development required for innovating technologies and developing new vaccines; and (iv) establish dialogue with civil society groups and organizations that work on human health development programmes, so that benefits and risks of vaccines are openly discussed and appreciated.
Delivery of vaccines through national programmes presents challenges of funding, timely procurement, storage, delivery and availability of trained medical and paramedical staff. India’s National Polio Surveillance Programme is credited with implementing the world’s largest and successful disease surveillance and immunization programme. The states of Tamil Nadu, Pondicherry and Kerala are noted for implementing routine immunization programmes that provide coverage to over 90 per cent of the target population. The lessons learnt through these programmes need to be quickly used for development of immunization plans for all states of India.
In turn, the plans of different states can be used for the development of a National Immunization Action Plan, with clarity on funding and staffing needs and timelines for roll-out of desirable vaccines at the national level. Funding for such an all-India plan requires national commitment and buy-in, and technical inputs from various national and multilateral stakeholders. But the returns on investments will be significant in terms of lives saved, human development and economic advance.
As mentioned before, the decision of selection of vaccines for national programmes requires reliable disease burden and epidemiologic data. The public health science base is growing and medical research institutions, including some prominent medical colleges, have conducted excellent disease surveillance and epidemiologic investigations. What are needed now are government-funded, multi-centre disease burden and epidemiologic programmes relating to diseases for which life-saving vaccines exist. Once available, such data can be promptly used by policy makers.
There is also need to develop multiple clinical trial centres for public health and vaccine testing. These centres will be a significant boost to the Indian vaccine industry, which needs to test new and improved vaccines in its pipelines.
Implementation of immunization programmes requires systems and processes that are well staffed and managed in a professional manner. The National Polio Surveillance Programme and the TB DOTS programme are there to learn from. Taking advantage of India’s excellent information technology (IT) and communication knowhow, programmes can be designed to monitor people who are vaccinated through electronic immunization records.
Such IT and communication systems can also be used for tracking inventories of vaccines at central and peripheral locations, documenting and acting on any adverse events, reaching out to clients who do not come for the required number of second or third doses of vaccines. An advantage of the electronic system of implementing and monitoring immunization programmes is that it would allow timely evaluation of quality of the programme. Consequently, this would allow policy makers and vaccine managers to make required changes to ensure proper coverage and timely administration of vaccines.
The critical component for a national immunization programme is support of the public and of civil society. Engagement with civil society groups can be facilitated by agencies of the government, but it has to include participation of scientific and medical experts and industry professionals. This discussion and debate should not be a one-time event, but kept alive – so that questions that emerge are adequately addressed openly and with technical and health inputs.
Industry has an obligation to engage with civil society and present facts regarding benefits of vaccines. Government agencies have an obligation of ensuring to the public and to civil society that effective regulatory systems are adopted in granting approval to vaccines for public use. As stated earlier, this should include post-marketing surveillance that is designed to detect the first signal of adverse effects.
Each of the above core elements would require commitments from academia, industry, regulators, civil society and government agencies. The end result of a coordinated Indian Vaccine Action Plan would save large number of lives every year. It would create a permanent environment for human and economic development.
India has played a critical role in making affordable vaccines that are used in many developing countries and are saving lives and preventing diseases. The opportunity and challenge now is to develop strategies and tactics to expand focus on R&D needed for development of new and improved vaccines, and to put in place an effective vaccine immunization programme that reaches everyone. At the heart of the issue is this equity – every Indian, rich or poor, deserves every vaccine that can help him or her.