Julien Potet from MSF describes the underlying causes limiting access to antisera in low- and middle-income countries.
What do snakebites, tetanus and rabies have in common? Answer: Treating patients with these life-threatening conditions relies on antisera, a class of immunoglobulin-rich products derived from the plasma of human volunteers or animals and used for passive immunization after suspected exposure (to tetanus or rabies) or for antivenom activity following snakebites. Each year about 55,000 people die of rabies and over 60,000 of tetanus, while snakebites kill between 20,000—94,000 people and lead to many more cases of permanent disability.
Another commonality is that all three types of antisera are extremely difficult to access in developing countries, due to several constraints that, in combination, produce a downward spiral of neglect. Manufacturing these products is relatively expensive and global sales are stagnant, so potential profits are low—which has gradually led several major manufacturers to abandon production. The withdrawal of these companies, in turn, has exacerbated the problem, opening the door to unstable supplies, further shortages and, given the lack of strong regulation, usage of sub-standard products.
The latest blow came in March when Sanofi-Pasteur told its clients that it may cease production next year of its crucial polyvalent African antivenom. Even before this development, the shortage of antivenoms in sub-Saharan Africa was dire: while two million vials are needed annually, less than 400,000 are produced. And today’s African antivenom market is dominated by two Indian products prepared with immunizing mixtures that do not contain venom of Echis ocellatus, medically the most important snake in West Africa; consequently, both products show low efficacy in this sub-region. New antivenoms, made in Latin America, have recently been developed for African markets, but they must be tested further to determine precisely their clinical efficacy in different African locations. In the meantime, Sanofi-Pasteur’s withdrawal would leave Sub-Saharan Africa without one of its best options.
In May, the World Health Organization (WHO) held a meeting with several antivenom producers to address the crisis. This initiative now needs to be translated into an action plan—starting with a commitment from Sanofi-Pasteur to continue production of its African snake antivenom, at least until a product with proven efficacy for a similarly broad range of African snake species can be identified or produced elsewhere. Ensuring continued supplies of this essential drug for envenomings (defined by WHO as a Neglected Tropical Disease, or NTD) would be consistent with Sanofi’s stated interest in, and contributions to, the fight against NTDs.
But these supply problems are not limited to antivenoms: People exposed to rabies and tetanus in developing countries are also almost completely out of quality-assured antisera. The global supply of human tetanus immunoglobulins is in jeopardy after Baxter stopped manufacturing them this year. As an emergency health care provider in regions where tetanus is prevalent, Médecins Sans Frontières/Doctors Without Borders (MSF) struggles to obtain sufficient quantities of quality-assured tetanus immunoglobulins on a regular basis.
Similarly, while administration of rabies immunoglobulins (together with the first dose of rabies vaccine) is recommended for most at-risk bites, access is severely limited even in middle-income countries; for example, a large retrospective study in Chengdu, China found that fewer than 10% of patients needing rabies immunoglobulins received them. In most of Sub-Saharan Africa, access is non-existent outside centers run by international NGOs and some private clinics.
The underlying causes for the erratic supply of these products are a mix of technical obstacles and financial disinterest. The production of human immunoglobulins is (rightly) subject to strict ethical requirements that limit output capacity, and the manufacture of antivenoms is a resource-intensive and time-consuming process. In addition, the financial incentives behind these products are weak, considering the small market for them in wealthy countries.
The result is that prices are unaffordable for low-income countries where the need is greatest. Equine rabies immunoglobulins cost US$25-$50 per dose, and human rabies immunoglobulins four times more. A single vial of Sanofi-Pasteur’s polyvalent African antivenom costs over US$100. Although treatment with antivenoms is highly cost-effective, these prices nevertheless represent huge burdens to ministries of health in poor countries. For MSF, antivenoms and immunoglobulins for tetanus and rabies accounted for nearly 30% of our 2011 budget for vaccines and vaccine derivatives, while representing less than 1% of the number of vials used for immunizations.
What can be done to turn this crisis around? One essential step is that donors finance implementation of a WHO quality-assurance program that can properly evaluate whether available antisera comply with the established norms and standards for assessing the efficacy, safety and quality of snake antivenoms and other products derived from animal serum. (Most drug regulatory authorities in developing countries cannot conduct their own evaluation, due to lack of resources.) For antivenoms this will require, among other things, establishing reference banks of venoms against which the efficacy of available antivenoms is tested regularly.
At the same time, a mechanism for ensuring availability and accessibility should be established, providing antivenoms and immunoglobulins free of charge to those who cannot pay. Multi-billion dollar initiatives for immunization such as the GAVI Alliance have a critical role to play in securing access to these products.
More than a century after Emily von Behring and Albert Calmette first experimented with passive immunization, antisera remain neglected therapeutics. In the era of genetic engineering, these blood-derived products may seem antiquated, but they are just as essential now as they were 100 years ago.
Julien Potet is the Paris-based Policy Advisor on Neglected Tropical Diseases for the Access Campaign at Médecins Sans Frontières.