The final part of the workshop’s last session featured visionary statements. The three panelists were Julio Croda, chief, Department of Communicable Diseases, Secretary of Health Surveillance, Brazil; Lori Burrows, associate director, Michael G. DeGroote Institute for Infectious Disease Research, Canada; and Peter Sands, executive director, The Global Fund to Fight AIDS, Tuberculosis and Malaria (The Global Fund). Moderated by Marcos Espinal, director, Department of Communicable Diseases and Environmental Determinants of Health, Pan American Health Organization, the panelists synthesized priority actions on cultivating innovative solutions to address emerging microbial threats that are sustainable, ethical, equitable, and focused on interventions that most effectively improve people’s lives.
Julio Croda remarked that developing the simplest and cheapest innovations is the best strategy to ensure that solutions are feasible and can be implemented across settings with different resource levels. He provided several examples of health innovations being delivered to the poorest populations in Brazil. Two arbovirus control innovations are being planned to scale up across the country.
One project involves large-scale release of Aedes aegypti mosquitoes with Wolbachia bacteria in urban areas to assess their effect on dengue fever and other vector-borne diseases, such as chikungunya and Zika (van den Hurk et al., 2012). Wolbachia are inherited intracellular bacterial symbionts
common in many mosquitoes, but not in mosquito species considered to be of major importance in transmitting human pathogens (Moreira et al., 2009). In Brazilian Aedes aegypti mosquitoes, Wolbachia has been found to block circulating Zika virus isolates (Dutra et al., 2016). Studies have also determined that this intervention reduces the transmission potential of dengue-infected Aedes aegypti (Ye et al., 2015). An ongoing clinical trial is looking at the effect of this intervention on the offspring of Wolbachia-infected and wild-type mosquitoes.
Another innovation, the Arbo-Alvo project, is a methodological proposal for risk stratification for dengue, chikungunya, and Zika in endemic cities in Brazil. Among the project’s goals are to evaluate and identify areas of increased risk for dengue transmission using local spatial statistics in certain territories. When combined with other innovations, this package can be used to optimize control of the arbovirus. The SISS-Geo platform was created in 2014 to assist in monitoring the health of wildlife in Brazil, in collaboration with communities, health professionals, the environmental sector, and researchers, through mobile devices and a web platform. Based on information from the platform, mathematical modeling can be used to predict the number of human cases of yellow fever and inform vaccination efforts.
Another project is using single-dose tafenoquine combined with G6PD rapid testing to track malaria transmission in northern Brazil. To address visceral leishmaniasis, researchers are implementing more than 2 million insecticide-impregnated dog collars in the regions of Brazil heavily affected by the disease. Finally, he noted that a prison-based tuberculosis intervention is being implemented, because mathematical modeling suggests that exit screening is more effective than entry screening to detect the spread of the disease in prisons and to reduce the spillover effect in the general community (Mabud et al., 2019).
Lori Burrows opened by citing a recent report by the Council of Canadian Academies, When Antibiotics Fail (CCA, 2019). She explained that although Canada has a strong health care system, it is somewhat fragmented because health care is delivered provincially, so each province has slightly different demographics, faces different problems, and monitors different indicators. This is a challenge for the development of national-level statistics, such as the number of people who actually die of drug-resistant infections, which was not available prior to this report. This illustrates why a problem needs to be clearly defined and quantified before government resources can be requested and deployed to address it, she noted.
To encourage government action, the report also clearly defines the
socioeconomic cost of failing to address antimicrobial resistance (AMR) in Canada. As of December 2019, 26 percent of infections in the country are resistant to first-line antibiotics; this is likely to increase to 40 percent by 2030, stated Burrows. She suggested that the estimated $1.4 billion in health care costs and $2 billion in lost gross domestic product currently associated with AMR will also increase commensurately. Another benefit of the report is that it contains stories and vignettes of real people who have been affected by AMR, she said, and engaging people at a personal level can garner more resources for a problem. Current work to address AMR in Canada is being supported by private donors who acquired drug-resistant infections themselves, as the government is not yet willing to provide funding.
Burrows emphasized that regardless of the setting’s resource level, dealing with drug-resistant infections requires cross-sector innovations in stewardship, surveillance, discovery, and economics. In the context of stewardship, she highlighted education as one of the keystones of addressing AMR. This should involve educating patients as well as physicians to decrease the prescription of unnecessary antibiotics, she said. Simply by training primary care physicians not to prescribe antibiotics for viral infections in children aged 0–14 years, the number of those prescriptions has decreased dramatically in that age group over the past decade in Canada, although similar decreases were not seen among healthy individuals middle aged or older (CCA, 2019). Cross-sectoral surveillance is required for monitoring pathogens and targeted deployment, she added. A recent World Bank report argued for building surveillance and management, integrated between human and veterinary medicine, in all countries, citing this as the most efficient and cost-effective solution to problems with antimicrobial resistance (Jonas et al., 2017).
In terms of economics, Burrows noted that new funding models and incentive models are needed. The pharmaceutical sector has divested itself significantly from antibiotic discovery given the risk of investing billions of dollars in developing drugs that could lose effectiveness owing to resistance within a short amount of time. She suggested that new ways to sell antibiotics are needed. For instance, an innovation is being piloted in Britain in a “Netflix-style” subscription model, whereby companies would develop antibiotics, and the hospitals and health care systems would pay into a subscription model in order to have access to those drugs if they need them. Another example is the nonprofit model used by Canadian Blood Services, which sends tenders out to companies to purchase large lots of factor VIII and factor IX, so that hospitals can directly request the products from Canadian Blood Services when they are needed, rather than requiring individual hospitals to procure the products themselves. She suggested that this existing infrastructure could be used to facilitate antibiotic stewardship, if the government were willing to do so.
Burrows stated that cross-sectoral innovations in discovery are already ongoing to develop new drugs, adjuvants, alternatives, vaccines, and diagnostics. She noted that in addition to being useful against viral diseases, vaccines are also useful against bacterial diseases and AMR (i.e., a person who is vaccinated against a bacterial disease and does not acquire the disease will not need to be treated with antibiotics). She works with Pseudomonas aeruginosa and Acinetobacter baumannii, gram-negative pathogens that are also opportunistic, which makes it challenging to determine whom to vaccinate, how often to vaccinate, and how to determine the efficacy of a potential vaccine. Bacteriophages represent a promising model for alternate ways to kill gram-negative drug-resistant pathogens. However, bacteriophages are not generally suitable for traditional clinical trials because they are so host specific—starting treatment with phages requires knowing the exact cause of a patient’s infection.
Preserving bacteriophages is another multifactorial problem. Work is ongoing to find ways to preserve them on the shelf at room temperature for long periods of time so people in lower-resource countries can have access to them. She added that in addition to new antibiotics, new nutritional interventions are also needed. For example, urinary tract infections are one of the most common reasons why people are prescribed antibiotics in the community. Taking D-mannose can help prevent Escherichia coli urinary tract infections (Domenici et al., 2016), although this would be difficult to monetize. She noted that microbiome interventions hold promise in preventing infections, but the field is still nascent and hampered by pseudoscience. In terms of diagnostics, pairing inexpensive, paper-based diagnostics with interventions such as bacteriophages could represent alternate ways to treat infections in low-resource countries.
Peter Sands explained that his organization is the largest multinational funding vehicle in global health, with an unprecedented $14 billion to spend through 2023. The Global Fund is not interested in innovation for innovation’s sake, he said. They are interested in innovation if it can be scaled to “move the dial” and make a difference in the delivery of the organization’s mandate to save lives and end the epidemics of HIV, tuberculosis, and malaria. As an organization, it has limited capacity to pursue innovations with interesting but marginal potential effects. In assessing innovations coming down the pipeline, The Global Fund focuses on the relative cost-effectiveness of new interventions versus expanding coverage of existing interventions, none of which are yet fully optimized. For instance, as a relatively cost-effective way to achieve greater effect, The Global Fund is
looking for better ways to deploy condoms. Although they are inexpensive and highly effective when used well, they are currently poorly deployed and used, leading to substantial differences in their effectiveness across settings.
Another priority for The Global Fund is for innovation to be deeply informed by insights from the communities that are affected by those three diseases, said Sands. He also observed that innovations need to be scalable. Small pilot projects can showcase interesting new technologies, but The Global Fund is focused on interventions that can work at scale to change the lives of hundreds of thousands or millions of people. For example, ongoing work around self-testing for HIV is not widely integrated into national AIDS programs, leading to a large falloff from treatment among people who test positive within small pilot programs. The Global Fund will channel $25 million in catalytic funding toward integrating self-testing programs into national programs, which it has identified as the best way to effect real change, he added.
Sands explained that The Global Fund is seeking innovations that work within their time frames and within their model of country-informed decision making. Most of the organization’s funding will be committed in signed grants for programs by the end of 2020, and the innovators with whom they work most successfully have a deep understanding of The Global Fund’s mechanisms. He noted that progress moves slowly in the health world, for many good reasons, but suggested that there may be room for greater focus on the “time value of money” measured in lives (e.g., the lives lost due to lengthy delays in changing treatment guidelines for tuberculosis and HIV to incorporate new and improved regimens). He observed that there is an iteration in innovation between efforts to develop tools and then find uses for them, and efforts to identify problems and then find the tools to solve them. His organization is engaging people in the innovation sphere around HIV, tuberculosis, and malaria so they are aware of the problems of greatest concern and so The Global Fund has an idea of the tools that innovation could bring.
Sands remarked on the types of innovations that might interest The Global Fund in its three disease areas. In HIV, the immediate focus is on driving change in prevention: innovation is needed to help address why adolescent girls and younger women have much higher infection rates in many parts of Africa (Karim and Baxter, 2019). He noted that this may involve biomedical innovation, such as a combination contraceptive and preexposure prophylaxis regimen, as well as innovation around how to address gender-based violence. Additional scalable innovations are needed to break down human-rights-related barriers to accessing HIV care that are faced by people who are criminalized, marginalized, and stigmatized; people who are transgender; men who have sex with men; prisoners; and people who inject drugs, among many others.
Another issue warranting innovation is effectively engaging asymptomatic men with HIV with health systems, because these men are a major source of ongoing infection. Sands said that in the area of malaria, The Global Fund is involved in a pilot for a promising vaccine candidate. Sands noted that innovations are urgently needed around vector control that are inexpensive and cost-effective, because the average spend per capita in settings where malaria is highly endemic is only about $4 per year. In tuberculosis, he said that progress toward a vaccine is further out but still encouraging. In the shorter term, inexpensive robust diagnostics that do not require a laboratory-style environment, as well as better strategies to find people who have tuberculosis and determine whether the strain is drug sensitive, would be impactful.
Espinal asked how parallel, vertical innovations and initiatives like those supported by The Global Fund can parlay into health system strengthening, particularly in lower-income countries. Sands replied that there is no contradiction between having a mandate around the three biggest infectious diseases and supporting health system development, because countries that have been able to eliminate those diseases have done so by building strong health systems. In settings with high burdens of those three diseases, health systems tend to become overwhelmed and focus primarily on treating those diseases. He added that The Global Fund is the largest multinational investor in health systems, investing about $1 billion each year (Sands, 2018).
Innovation is also needed around health systems and particularly around community health worker models, on which the most resource-poor countries are dependent. Finding ways to use technology to support community health workers could help reduce their paperwork burden. He said that innovation in financing models would benefit countries with large informal economies where traditional tax or insurance modes of financing health do not work well. Croda highlighted the need to incorporate innovation in resource-poor countries without strong health systems by engaging policy makers to invest in innovation. Burrows commented that climate change needs to figure into these conversations, because many of the issues being discussed, such as migration and disease transmission, are the consequence of inequalities caused by climate change.
Rafael Obregón remarked that governments often lack the resources and capacity to evaluate the range of innovations and technologies available. He asked about how to support governments in deciding which innovations to move forward with, such as by helping to streamline decision-making processes. Sands responded that one strategy is for countries to channel their assistance on the three major infectious diseases through The Global Fund,
which lessens the coordination costs of multiple different actors and provides a model by which the decision making is located in-country through the country coordinating mechanism. In settings where this strategy is feasible, working with local systems (e.g., government malaria agencies) is effective in addressing the diseases and building local capacities simultaneously, he said.
Audrey Lenhart asked about the level of evidence that would be sufficient to justify scaling up innovative interventions nationwide, such as the Wolbachia intervention in Brazil or the malaria vector control interventions supported by The Global Fund. Croda replied that the Wolbachia intervention will be supported by evidence from the ongoing phase 3 study. Governments are interested in a business plan to support these types of new innovations, he added. In HIV, for example, introducing a new drug and documenting how it has controlled transmission and reduced incidence can be used to inform the business plan to encourage governments to scale up the innovation.
Sands commented that in the context of next-generation bed nets for malaria, scale up of the pilot programs is currently constrained by manufacturing capacity. When that issue is resolved, the focus will be on deciding whether there is enough evidence to start scaling up in areas with the most prima facie evidence of vector resistance to the existing pyrethrum-based insecticides. This involves a complicated mix of scientific considerations about evidence-based decision making and ethical considerations—such as whether the interventions should be used in settings where the existing nets are not working as well—and communication issues. If confidence in the existing nets is undermined prematurely, then large numbers of existing nets might go unused. He added that stratification is another consideration. Understanding where resistance is located can ensure that those settings are targeted with the new nets, which are more expensive than the old nets. Sands concluded by highlighting the complicated trade-off between rolling out older nets to people who are not covered at all and upgrading the nets for those who are at the greatest risk.
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