Protecting Research and a Case for Optimism

![Figure][1] Bill Gates PHOTO CREDIT: BILL & MELINDA GATES FOUNDATION This Editorial is based on a presentation given at the 2013 David E. Barmes Global Health Lecture: Why the Future Needs Biomedical Innovation. The NIH lecture series honors the late David Edwards Barmes and his dedication to improving health for citizens of the developing world ([ 1 ][2]). More than 30 years ago, Microsoft was built on a democratizing idea: putting the power of computers at the fingertips of billions of people. Creative and dedicated colleagues devised and tested bold strategies to turn our idea into a reality. Nearly 15 years later, I began to learn a bit about infectious diseases that don’t exist in the United States but afflict hundreds of millions in the developing world—such as malaria, which is caused by Plasmodium species and spread by mosquito bites, or rotavirus, which is merely a nuisance in wealthy countries but a killer in poor countries. It was clear that the innovation leading to breakthroughs every day in the tech industry was not being applied to one very serious problem that needed solving: stark global health inequity. My wife Melinda and I started the Bill & Melinda Gates Foundation ([www.gatesfoundation.org][3] ) to help change that dynamic. As with the computer industry, progress in global health starts with pointing scientific research and innovative thinking in the right direction. For example, the world needs vaccines against infections caused by HIV (AIDS), Plasmodium species (malaria), and Mycobacterium tuberculosis (Tb)—none of which renders the patient immune to reinfection. Thus, in each case the vaccine must do something that typical vaccines don’t do: induce protection superior to that achieved by natural infection. Although this is a daunting challenge, conjugate vaccines provide a precedent. These vaccines build on very old basic research on the pneumococcus bacterium and its cell-surface composition. In the 1920s and 1930s, a group of researchers discovered that pneumococcal cells are surrounded by a polysaccharide capsule that is not strongly immunogenic, but that conjugating a protein to the polysaccharide increased the ability of the polysaccharide to stimulate an immune response ([ 2 ][4]). Encapsulated bacterial pathogens are a major cause of repeated childhood infections, in part because the antibody response to polysaccharides is particularly weak in young children. The discovery by Avery and Goebel suggested a way to help the immune system do better than it does in the context of natural infection. It took more than 50 years, however, to translate this fundamental discovery into the launch of the first conjugate vaccine in the United States, against Haemophilus influenzae type b—work that was both supported by and conducted at the U.S. National Institutes of Health (NIH). Conjugate pneumococcal and meningococcal vaccines then followed, dramatically reducing the burden of disease in the developed world. But another 30 years passed before the launch of a conjugate vaccine specific for the developing world, the MenAfriVac meningococcal vaccine. MenAfriVac targets the serogroup A meningococcus prevalent in the sub-Saharan Africa meningitis belt and costs less than US$0.50 per dose, making it affordable for African governments. To develop a vaccine at that price, the partnership led by PATH and the World Health Organization brought in an emerging-country vaccine manufacturer, procured raw materials from a Dutch biotech company, and arranged a technology transfer from the U.S. Food and Drug Administration (FDA). Translating innovative research into global health products requires a sensitivity to the needs of the target area and the willingness to take an innovative approach. Vaccines are particularly important when it comes to ensuring that all people, no matter where they live, have the opportunity to lead healthy, productive lives. That is why our foundation is focused on the difficult research into vaccines against HIV, malaria, and Tb. Take HIV vaccine research, for example. HIV-infected individuals can produce antibodies that neutralize diverse strains of the virus, but these antibodies always trail the infection. Today’s antibodies protect people from the virus that they had yesterday. However, if we could somehow help people create protective antibodies before they’re infected, we’d have a vaccine. Technological advances in single-cell analysis and immunoglobulin gene sequencing have illuminated the path by which these broadly neutralizing antibodies are induced. Simultaneously, advances in structural biology and computational algorithms have revealed how antibodies neutralize HIV and how the virus escapes this fate. Together, these advances make it possible to define the immune response an effective vaccine might mimic and then attempt to design antigens for such a vaccine. Five years ago, none of this was conceivable. Now, researchers are using these advances to remove some of the trial and error from the vaccine development process. Part of this surge in progress is due to the positive-feedback cycles in technological development; part of it is the result of the genomics revolution and other technological tool breakthroughs. One day, when today’s advances lead to next-generation breakthroughs, we will be able to look back and connect a chain of discoveries leading to a successful HIV vaccine. As the history of conjugate vaccines shows, this chain of discoveries will be grounded in basic research. Unfortunately, the current budget constraints threaten to stunt the basic as well as the translational research that the NIH and other agencies foster. I hope the budget changes do not squelch scientific research and the training of new investigators. We stand at the threshold of discoveries that will point the way to an HIV vaccine and to new approaches for the prevention and treatment of malaria and Tb. We have reached this threshold because we have continued to invest in the science that leads to innovations with impact in the real world. The innovations happening in laboratories around the world are what enable humanity to accomplish more with less. Innovation is why I am optimistic about the future. It would be a shame if, to solve short-term budget issues, we made short-sighted decisions that will have negative long-term consequences. 1. [↵][5]David E. Barmes Global Health Lecture at the NIH (2 December 2013); available at [http://videocast.nih.gov/.][6] 2. [↵][7]1. O. T. Avery, 2. W. F. Goebel , Chemo-immunological studies on conjugated carbohydrate-proteins. II. Immunological specificity of synthetic sugar-proteins. J. Exp. Med. 50, 533 (1929). doi:10.1084/jem.50.4.533 pmid:19869644 [OpenUrl][8][Abstract][9] [1]: pending:yes [2]: #ref-1 [3]: http://www.gatesfoundation.org [4]: #ref-2 [5]: #xref-ref-1-1 "View reference 1 in text" [6]: http://videocast.nih.gov/summary.asp?live=13311 [7]: #xref-ref-2-1 "View reference 2 in text" [8]: {openurl}?query=rft.jtitle%253DJ.%2BExp.%2BMed.%26rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.50.4.533%26rft_id%253Dinfo%253Apmid%252F19869645%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [9]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamVtIjtzOjU6InJlc2lkIjtzOjg6IjUwLzQvNTMzIjtzOjQ6ImF0b20iO3M6MzE6Ii9zY2l0cmFuc21lZC81LzIxNC8yMTRlZDIxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==