BMJ  2008;336:750-753 (5 April), doi:10.1136/bmj.39497.598044.BE

Analysis

Rethinking global access to vaccines

¹ University of Pennsylvania School of Medicine, 3434 Sansom St, Philadelphia, PA 19104, USA , ² Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

Barriers to dissemination of life saving vaccines in low income countries can and should be overcome, argue Dave Chokshi and Aaron Kesselheim

Inadequate access to vaccines in low and middle income countries results in more than two million deaths each year.¹ Two thirds of these deaths occur in children under the age of 5. Hepatitis B virus and Haemophilus influenzae type b (Hib) vaccines are now starting to be used in low and middle income countries, but they were licensed for use in the industrialised world more than two decades ago. Our difficulty in disseminating well established vaccines casts doubt on our ability to promote widespread use of new ones, such as those for diarrhoea associated with rotavirus infection and for human papillomavirus (a causative agent of cervical cancer) (table). Currently, over 99% of the 440 000 annual deaths from rotavirus associated diarrhoea and 93% of the 260 000 annual deaths from cervical cancer occur outside the 60 wealthiest countries.^{2 3}

View this table: [in this window] [in a new window]   Development and dissemination of rotavirus and HPV vaccines

 

Challenging widely held beliefs

Three arguments have historically dominated discussions about the cause of unequal access to vaccines in poorer countries: the primacy of healthcare infrastructure; constraints imposed by insufficient funding; and the belief that vaccine approval in high income countries is a precondition for discussing access in other settings. Recent experiences have shown how each of these contentions is open to challenge.

Primacy of infrastructure
Must poor healthcare infrastructure be addressed before large scale vaccination can succeed? The claim that poor infrastructure is a more fundamental—and therefore more pressing—problem than access to vaccines must be distinguished from the claim that local logistical hurdles must be overcome to achieve equitable access. Those who agree with the former contention believe that ensuring supplies of food and clean water and building roads will do more for public health than isolated interventions like vaccines. For example, access to rotavirus vaccination has been questioned on the grounds that it might undermine the urgency of providing clean water and sanitation for all.⁴

An exclusive focus on the primacy of basic public health interventions, however, can block the opportunity to build infrastructure through vaccination. Empirical analyses, most notably of polio eradication in the Americas, have documented how immunisation programmes can strengthen the infrastructure of health systems.⁵ Amartya Sen describes the broader effect as an "autocatalytic process" connecting health and development, whereby improving health through direct means such as vaccines unlocks the capabilities of populations to thrive economically.⁶ In addition, contact between the healthcare establishment and indigent people is often sporadic and usually related to an acute health problem. Vaccines are one of the few interventions that can save lives even when healthcare infrastructure is inadequate or non-existent. Clarifying the underpinnings of this infrastructure problem permits a rigorous examination of the local obstacles that make the delivery of vaccines difficult.

Funding
Are the costs of closing the global vaccination gap out of proportion to the funding available? The Global Alliance for Vaccines and Immunization (GAVI) has collected almost $7bn (3.6bn; 4.7bn) since its inception in 2000. A pilot "advance market commitment" to help speed the development and availability of a pneumococcal vaccine gained seed funding of $1.5bn in 2007. Yet these commitments pale in comparison to the $35bn that GAVI estimates it would take to carry out its existing programmes in the 72 poorest countries through 2015.

At the country and district level, acceptance of the cost-funding orthodoxy has been posited as a chief reason for the slow uptake of vaccines such as for hepatitis B vaccine in the past.⁷ One reaction to this imbalance is to calculate the funding shortfall and advocate for its redress.⁸ But the vaccine equation is more complicated than simply tabulating inputs and outlays. Rational policy making depends on analysis of both costs and benefits. A recent cost effectiveness analysis showed that a vaccination programme for hepatitis B was both cost effective and affordable in the Gambia, where the per capita gross domestic product is only $300.⁹ Furthermore, vaccines can confer macroeconomic benefits such as improved labour productivity that may supersede the substantial directly measured health benefits.¹⁰ The International Finance Facility for Immunisation (www.iff-immunisation.org), which provides immediate aid from wealthier countries to GAVI, is a financial solution that represents a first step in accelerating the pace of investment in immunisation.

Prior approval
Must vaccines be developed for and approved by wealthier countries before they can be widely disseminated? Currently, availability of vaccines in low and middle income countries depends largely on prior evaluation by US or European drug regulatory agencies.¹¹ Pharmaceutical manufacturers receive the vast majority of their revenues from wealthier countries, so there is less financial incentive to make a product available if it is not being sold in those markets. Also, health agencies in poorer countries often take their cues from nations with more established regulatory systems before approving new products or when removing them from the market. In 2001, after Wyeth’s rotavirus vaccine Rotashield was taken off the market in the US for a rare association with increased rates of intussusception, Wyeth stopped production and the product was eliminated from use in low and middle income countries, where the higher rates of morbidity from rotavirus associated diarrhoea may have made the low risk of that side effect more tolerable.¹²

Under this paradigm, intellectual property rights can slow the dissemination of vaccine technology. As a result of the TRIPS agreement (the World Trade Organization’s agreement on trade related aspects of intellectual property rights), patents protecting drugs and other healthcare technology are becoming increasingly prevalent. Because patents provide manufacturers with full control over how their products are distributed, for innovative products such as human papillomavirus vaccines, global society is forced to ask: what is the manufacturer’s plan for making its vaccine widely available?¹³ Differential prices offered by pharmaceutical manufacturers may still remain too high, and implementation of donation programmes has been slow.¹⁴

Instead, the public health community should better regulate intellectual property so that new vaccines can reach the people who need them. While protecting markets in wealthier countries to help provide incentives for research and development, we should work to accelerate international cooperation that can lead to improved distribution in needy settings. For example, many vaccines derive from publicly funded research, and the clinical trials used to support regulatory approval in wealthier countries are often conducted elsewhere. The human papillomavirusvaccine Gardasil was originally researched by scientists at an Australian university, two American universities, and the US National Cancer Institute, and some of the early trials supporting its efficacy were conducted in Brazil, India, and Costa Rica. Wealthier countries’ governments could use this leverage to make the approval of future vaccines contingent on the existence of robust plans for global distribution. Novel licensing schemes have been proposed to speed technology transfer from larger innovator companies to local or regional manufacturers as soon as efficacy has been established.¹⁵ Such arrangements could help meet international demand for low cost products and permit rapid clinical testing needed to determine if a product is indicated for use in low and middle income countries.

Capacity building: a strategy to improve global vaccine access

In moving from defining the problem to outlining solutions, multinational efforts should focus on building local capacity to scale up vaccination programmes. Specifically, capacity building consists ofconstructing a parallel clinical research pipeline for developing countries, lowering barriers to vaccine production indeveloping countries, and fostering local leadership in healthcare delivery.

Clinical research capacity
Efficacy trials for vaccines could take place in parallel in several epidemiological settings to account for differences in disease ecology. The key phase III trial submitted for approval of one rotavirus vaccine (Rotarix) did not include any patients in Africa or Asia;¹⁶ the key trial for another (Rotateq) included patients from Taiwan but no other Asian or African patients (table ).¹⁷ Such decisions can have direct bearing on availability of vaccines—for example, 20 months after the publication of these landmark rotavirus vaccine trials, the World Health Organization stated, "Until the full potential of the current rotavirus vaccines has been confirmed in all regions of the world, WHO is not prepared to recommend global inclusion of rotavirus vaccines into national immunization programmes."¹⁸

Such caution can be well founded. In 1989, WHO recommended the high titre measles vaccine for use in low income countries. The vaccine was subsequently found to be associated with a twofold increase in mortality among girls and withdrawn from WHO recommendations.¹⁹ Such examples highlight the need to conduct parallel clinical research in low and middle income countries of both vaccine efficacy and overall mortality, and also to ensure that introduction of vaccines is organised so that individual and population outcomes can be assessed systematically. Responsibility for monitoring of vaccine research and development should fall to the public sector—or public-private partnerships—to minimise delays in cases where vaccine manufacturers did not pursue efficacy testing in countries where diseases are endemic. Such parallel research would expand scientific capacity, encourage performance of more appropriate and ethical clinical trials,²⁰ and produce results that would better inform governments’ risk-benefit calculations for investing in the vaccines. The Serum Institute of India demonstrates the necessary components of a parallel research enterprise: vaccine development in partnership with the public sector (the Indian government), rapid transfer of innovative technology (as with production of its Hib vaccine using a novel process from the Netherlands Vaccine Institute²¹), and scalable production extending internationally (seen in its collaboration on a vaccine against meningococcus for the "meningitis belt" of sub-Saharan Africa²²).

Local vaccine production
Once a vaccine is developed, prompt and adequate distribution requires inexpensive scaled production. Production capacity becomes even more important if the vaccine is produced from a non-traditional research partnership like the Malaria Vaccine Initiative rather than a large pharmaceutical company. Achieving necessary production capacity may require reliance on pharmaceutical manufacturers based in low and middle income countries.²³ Many such manufacturers have embraced a business model specialising in high volume, low margin production, which—with cost advantages in raw materials and labour—leads to lower cost products.²⁴ Some, including those in India, China, Brazil, and Indonesia, are successfully competing in the generic drug market in wealthier countries and have begun to invest in novel research and development.²⁵

The public health community could take better advantage of progress in manufacturing processes and the production scale of local manufacturers. For example, in addition to affordable licences for intellectual property protecting end products, as vaccines grow more biologically complex, manufacturers in developing countries may need access to specialised technology. The US National Institutes of Health has pioneered a programme to transfer manufacturing technology to public and private institutions in low and middle income countries and has transferred early stage technologies for meningitis, rotavirus, typhoid fever, dengue, and varicella vaccines, building innovative capacity as well as production capacity.²⁶ If other public sector groups, such as universities, and private sector manufacturers emulate such technology transfer, intellectual propertycan serve as a tool to manage research collaborations rather than an impediment to access.²⁷

Procurement organisations must communicate with vaccine manufacturers to reduce uncertainty in demand. To preserve competition in the vaccine supply market, this communication could take the form of evidence based forecasting of disease burden and available funding rather than contractual agreements.²⁸ Providing manufacturers with information about new market potential could facilitate the efficient allocation of resources for developing, producing, and marketing new vaccines.

Local leadership
Calls for strong, country level leadership on vaccine introduction are common, but they are seldom followed by inquiries into why immunisation is not a higher priority for national leaders. One explanation is the poor quality of evidence about the value of introducing vaccines into low and middle income countries²⁹. More data are therefore needed on disease burden, economic consequences of vaccine introduction, and use of vaccines in existing public health programmes. The 2002 launch of accelerated development and introduction plans (ADIPs) by GAVI for pneumococcus and rotavirus vaccines sought to address these knowledge gaps.³⁰ These programmes have had some success building evidence bases, but they have drawn criticism by focusing on a few products developed by large pharmaceutical companies, while excluding others that may be more appropriate in low and middle income countries. In the case of human papillomavirus vaccines, the non-profit organisation PATH launched a pilot project in 2006 to gather evidence to support introduction of the vaccine in India, Peru, Uganda, and Vietnam.³¹

Bridging the "implementation gap" between our growing knowledge of disease control and the implementation of that knowledge³² requires real time operational research, which focuses on processes as well as outcomes. Research on improving healthcare delivery systems creates widely applicable knowledge that addresses fundamental questions across various contexts.³³ One such question for vaccines is: how can immunisations be effectively packaged—both with other immunisations and different types of interventions—to take advantage of economies of scale and prevent the fragmentation of health systems into disease specific programmes? Implementation studies turn attention to health systems improvement as a measure of success, not just efficacy of a particular intervention.

The non-profit organisation Partners in Health (www.pih.org/home.html) provides two striking examples of success in changing the research paradigm: the use of community health promoters to provide antiretroviral therapy in resource poor settings,³⁴ and a novel therapeutic delivery system for multidrug resistant tuberculosis.³⁵ However, recent estimates are that less than 0.02% of health expenditure in low and middle income countries is devoted to implementation of health services research.³⁶ Research institutions in both the developed and developing world—and, in the best case scenario, collaborations spanning both—must enhance their commitment to this area.

The ultimate aim of any effort to improve global access to vaccines must be to show local leaders in health care and government the benefits of vaccination.³⁷ Local political leadership, when combined with international financing mechanisms, can increase investment in health, prioritise disease prevention, and raise awareness about the individual benefits of vaccination.³⁸ The way forward—building immunity by building capacity—would help save and improve the lives of millions of patients around the world.

Summary points Delay in distributing vaccines where they are needed most has a devastating human cost Many of the reasons proffered for the disparity in vaccine distribution between rich and poorer countries can now be challenged with new evidence and better understanding of the underlying problems Wider global availability of affordable vaccines can be achieved through building local or regional clinical trial and vaccine production capacity Implementation research, by directly demonstrating the benefits of vaccination, can spur country-level leadership

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Contributors and sources: Both authors contributed to the research, writing, and revision of the manuscript. This article arose via dialogue with Adel Mahmoud, Brian Strom, Art Caplan, and Heidi Williams. DAC is guarantor.

Funding: None.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

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(Accepted 16 January 2008)

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