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Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
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3

Vaccine Research and Development

Global coordination and funding for vaccines and other medical products needed in a pandemic must happen beforehand; it is also logical that the research and development (R&D) would ideally be in advance. But financial and business incentives are often not designed to enable this type of research to take place at the necessary scale. Numerous challenges also exist related to different types of technology, data sharing, and equity. With the wealth of research conducted during the coronavirus disease 2019 (COVID-19) pandemic, many lessons have been learned that can inform future pandemic planning, especially for influenza. This chapter highlights promising technology for the future of R&D, areas that can be improved upon after the experiences in 2020, what investments should be prioritized to better prepare for emergency events, and how influenza and other pandemic planning can be enhanced, including ways to improve equitable access of medical products.

EXPLORING PROMISING TECHNOLOGY AND STEPS FOR THE FUTURE

Beverly Taylor, head of Influenza Scientific Affairs, World Health Organization, and International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Lead, Seqirus Vaccines, asked panelists what they saw as promising technology for the future. Charu Kaushic, chair of the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) and scientific director of the Canadian Institutes of Health Research, highlighted the many platform technologies and vectors that have

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

played a very important role in the COVID-19 pandemic because they have been funded across the pipeline for the last several years and were now ready to go. She called attention specifically to the Coalition for Epidemic Preparedness Innovations (CEPI), which focuses primarily on pandemic preparedness platforms, and the investments it has been making in diagnostics and sequencing technologies since its inception in 2017. “We need to learn lessons from what we’ve been through so far,” she said, “and there is a lot of appetite within government and coordination to increase investments in public and private pandemic preparedness funding.” While the mRNA technology has recently played a pivotal role in the current success of vaccines, she said, it had been studied for more than 20 years. It was not until nanoparticle technology was optimized that the combination of the two really made it feasible for a successful vaccine to be created.

Maria Elena Bottazzi, associate dean of the National School of Tropical Medicine at the Baylor College of Medicine, commented on her experience from an academic vaccine center involved in product development partnerships across disciplines. She said they have been quite successful using conventional platforms of protein-based vaccines but recognized that they do need to bring in alternative, innovative technologies. However, she sees opportunity for combining them and determining if there are roles for them, perhaps priming with an RNA technology and then boosting with a conventional technology. Additionally, beyond just the platform to produce candidate vaccines, she highlighted formulation science, where adjuvant technologies can be critical, also combined with affordability, scalability, and accessibility. She suggested remaining open to many different types of technologies, using an example of a hookworm vaccine that uses a tobacco plant expression system or others using yeast, insect cell, or bacterial systems. Finally, they are interested in examining innovative routes of delivery, aside from intramuscular, and different vaccine schedules.

Highlighting novel manufacturing platform systems, Carolyn Finkle, chief operating officer at Medicago, described their system that uses plants for recombinant protein expression and added that the company is working on phase three trials for a COVID-19 vaccine. In the future, she said, it will be important to have multiple tools to fight against pandemics, including platforms with the ability to quickly obtain the sequence and express the protein in order to rapidly move to production. For this process to happen as seamlessly and efficiently as will be necessary, she said that continued, enhanced public funding for academic research is needed, knowing that a lot of that information will eventually be translated into a product. She also noted opportunities for surrogate measurements in terms of regulatory response, and though no correlates have been established for SARS-CoV-2, they have been demonstrated in influenza—for example, with the hemaglutin antibody titer. She was hopeful regulatory bodies can move forward to

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

adopt correlates for vaccine efficacy, especially within the influenza frame, and accept other surrogates that can be predictive of vaccine efficacy, such as cell-mediated responses. All of this could lead to more rapid vaccine development and approval but requires coordination between government, industry, and regulatory bodies.

AREAS FOR IMPROVEMENT

Despite clear success stories within the R&D environment, participants indicated that many areas have emerged that could be improved for future responses. Kaushic commented that the successes should be celebrated, and she remarked at how unlikely it was 1 year prior to think that so many people would have access to several effective vaccines. But while 1.5 billion people have received the vaccine, 5.5 billion have not.1 Without equity in access, she said, no one will be free from the pandemic, and she added to Bottazzi’s points about ensuring technology, infrastructure, and capacity is distributed not just in the Global North but also throughout the Global South and low- and middle-income countries. Demonstrating the current inequity, she explained that GloPID-R tracks investments in research: of the $4.5 million invested across more than 10,000 research projects, less than 1,000 have gone to the Global South. She estimated about 350 projects have been funded in Africa, compared to North America, with more than 6,000. Kaushic also shared concern that without a large network of capabilities built in the Global South, the pandemic will spread in unvaccinated areas until it settles into a seasonal pattern like other coronaviruses.

From a manufacturing standpoint, Finkle highlighted the gaps in domestic capability in many places, resulting in some countries suffering more than others, as Kaushic mentioned. In addition to trying to enhance domestic capability, she also saw a need for avoiding raw material supply shortages, which has been an issue for many vaccine manufacturers. This could be done through better coordination, more funding for raw materials, or working with the World Trade Organization to eliminate trade and regulatory barriers to adoption of practices for export to facilitate and expedite cross-border supply. As part of this, though the unprecedented time line of the COVID-19 vaccines was in part due to good coordination with regulatory authorities, she also saw areas for improvement on issues such as facility inspections and other innovations related to manufacturing and regulation. Finally, Finkle called for unhindered access to the pathogens and samples to support the development of new products, but this would also rely on multiple validated manufacturing platforms being ready. Taylor echoed this need, alluding to what a different situation the world would be

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1 At the time of this workshop on May 25, 2021.

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

in if the genetic sequence data from SARS-CoV-2 had not been shared so rapidly to enable awareness of emerging variants.

From her perspective within the vaccine center, Bottazzi highlighted “continuity of the ecosystem” as an area in need of improvement and dedicated investment. She shared an example from their work on a prototype severe acute respiratory syndrome vaccine beginning in 2011 that received generous funding because of the epidemic in 2003. They met the required milestones but then had no clear next steps because it was no longer considered a priority. She posited that if the work had continued and they were able to maintain and continue evaluating the products, it could have enabled more accelerated access to data and information related to other coronavirus vaccines. Having better continuity in the future, including having funders aligned in the various areas of the ecosystem of development, will be very important, Bottazzi emphasized. She also pointed out the need to think about technology transfer early in the process, including the framework of how the scale-up and production will work, identifying who the partners are and what level of capability they have—especially with novel technologies. While it is clear these things can be done with money and urgency, the sustainability aspect is what really needs to be improved, she concluded; influenza has had some of that continuity because of its seasonality, but this should be expanded.

Global Preparedness Network and One Health

Throughout the discussions, two specific areas of improvement were mentioned in relation to R&D. Kaushic highlighted the discussions at the 2021 G7 and G20 meetings around a Pandemic Preparedness Network, which would be critical for global coordination efforts to ensure more successfully completed vaccination efforts around the world and support developing strong infrastructure and capacity for technologies for vaccine manufacturing and clinical trials in the Global South. Additionally, she called attention to the emergence of pandemics resulting from interactions between the environment and climate change. Changing climate patterns allow pathogens to survive in new environments, while urbanization and changes in human behavior lead to greater exposures and interactions between humans and animals. Human health needs to be connected to the environment and animal health, but investment has historically been insufficient, she stated. Specifically examining investments from the World Health Organization R&D blueprint, she noted that this point of One Health has not been an area of strength and remains underfunded and underexamined.2 These are areas we can improve on, she said.

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2 One Health is discussed at greater length in Chapter 2.

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

CRITICAL RESEARCH AND DEVELOPMENT INVESTMENTS NEEDED

Taylor reiterated that the world cannot be doing development in the time of a pandemic, noting that funding during “peacetime” is critical to maintain forward momentum and lead to a robust response. Finkle added that the manufacturing infrastructure needs to be in place in order to be scaled to the levels necessary for a global response. She again highlighted the influenza platform that Medicago had already validated that was able to be adapted for COVID-19. An important investment is funding, Finkle noted, such as government funding for research and technology development that is ongoing so efforts are sustainable and can be ready when needed. This way, she said, when a pathogen emerges, the world will have not only validated platforms but also precursors in R&D.

Bottazzi acknowledged that factories, infrastructure, and a good workforce are all important, but what is really needed is a strong quality management system and regulatory framework prepared and ready—especially in countries that are still striving to reach a high level of stringency. This is what makes sustainability so complex, she noted—all the work that happens is surrounded by the need for quality management, and those agencies doing review and approval need to be trained and appropriately qualified. These aspects need to be included in funding for a more holistic picture of what is needed for a robust response, she said. When you bring in novel technology, regulators have to understand that they need to learn along the way, so their sustainable funding is important as well. She also advocated for strong clinical trial networks together with manufacturing networks, both of which communicate with one another. Bottazzi commented on the huge regional gaps for manufacturing capacity, such as in Africa and Latin America, and the importance of technology transfer. “Everyone wants to enable the new mRNA technology,” she said, “but we also need to maintain the warm base of old conventional technology while bringing in new platforms.” Funding this ecosystem of technology transfer can increase self-sufficiency by other regions, leveraging and expanding the Developing Country Vaccine Manufacturing Network to other regions of the world.

Ran Balicer, chief innovation officer at Clalit Health Services, reiterated Finkle’s points on investing in correlates of immunity. It has been difficult thus far to understand what can be trusted in terms of numerals or cellular correlates. While any future vaccine will need to be understood before it is put in the field, or see what happens in terms of actual morbidity, he admitted this is a very tricky issue and will need more funding and more infrastructure to get right. In addition, he also advocated for every country to begin putting in place a set of ready laboratories that are able to conduct ongoing, systematic surveillance in real time and provide a systematic

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

sample of a new pathogen. Bottazzi echoed the need for more proactive surveillance that can continue during the interepidemic period. Alongside epidemiology and genomic surveillance is the need to prepare clinical trial sites and have agreements set for data sharing—using influenza as a potential model and framework.

Kaushic noted that many investments have not come to fruition because of the fragmented networks and clinical trials. One of the successes of COVID-19 has been the ability to run Phase 1, 2, and 3 trials more or less in parallel. She acknowledged some at-risk investment on the part of government needed along with the ability of regulatory agencies to be open to new ideas. She also saw a need for forming large international clinical trials networks based on developing common protocols that can be adapted to local needs on the ground. Emphasizing the need for funders to focus on how to think about and execute this better in between epidemics, she said, “We need to invest funding and run clinical trials in places where the pandemic is.” Finally, Kaushic called for investment in social sciences. For example, a vaccine will only be as good as its uptake, so without vaccine confidence, populations will not reach the levels of protection needed. Balicer reiterated this, noting the detrimental effect the “infodemic”3 of false information had on many around the world, sometimes contributing to morbidity because people refrained from steps that would have helped them. He also called for more use of behavior economics to tackle some vaccine hesitancy issues.

ENHANCING FUTURE PANDEMIC PLANNING

Clalit Health Services, the largest health care system in Israel, serves approximately 4.5 million people. Balicer shared Clalit’s experience during the pandemic, saying that it tries to focus on real-world studies, performing a large-scale, real-world assessment of the actual effectiveness of a vaccine after the efficacy trials are completed. But the challenges are immense, he noted, as working with so many different institutions demands the right level of specialty and staff in each one. The staff and corresponding institutional knowledge need to be maintained across epidemics on an ongoing basis to avoid serious gaps in time between opportunities to actually implement and conduct trials. He advocated for a way to maintain a nucleus of personnel and institutions that have the expertise to collaborate; no mechanism for this exists, and it is difficult to create for every emergency. Balicer added that the ability to perform Phase 4 trials or other big data–-

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3 An infodemic is an information epidemic, one that is characterized by a wave of information, including misleading or false information, that can have harmful effects on individual or population health. See more at https://www.who.int/health-topics/infodemic (accessed August 11, 2021).

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

driven assessments is contingent on the level of data quality. Improving this quality requires ongoing investment—this includes the right type of diagnostics done in real time, quality assurance, and a level of maintenance of the datasets to examine demographics or other covariates. “If there is one thing COVID-19 has taught us,” he added, “it’s that these types of real-world studies are a critical complement to the classic clinical trials—to help us understand effectiveness, side effects, and safety—but they require a dedicated infrastructure.”

Bottazzi reinforced the importance of the right data for real-world studies but also highlighted the need to understand where the real-life exercises will happen to allow the sector to go backward and design vaccines that are needed or learn from the experience to develop future products. However, without the sustainable financial and business models to support these different types of efforts, it becomes a difficult and fragmented process to bring a vaccine candidate or other product to fruition. She pointed to existing funding sources at early and late stages of development but described a gap in the middle, preventing continuity. Balicer agreed, saying that if the world wants things to go differently, it needs a different infrastructure. If the next pandemic is influenza, which many experts predict is highly likely, even if a vaccine is developed rapidly, the same questions will arise. For example, how well is the vaccine working, and is it as safe as it should be? Balicer said,

Until it occurs, we won’t know where the hot spots around the world will be, or what the number of infections will be like for different populations. In the case of COVID-19, even if there were amazing vaccine effectiveness assessment platforms in Australia or New Zealand, they would have been useless because they’ve had nearly no cases. Also given the possibility of waves or seasonality, we will need to have the right systems ready and set to work in near real time, but we currently do not have anything remotely close to this.

Balicer noted the lag that occurs in obtaining data on seasonal influenza each year and the number of unknowns trying to understand actual vaccine effectiveness for different age groups in different parts of the world. The current ability to draw practical conclusions from the data to policy making is lacking. He called for sustainable funding for these systems to ensure that people can trust the annual data, so that in an emergency, the response will be timely and have accurate information. Bottazzi added that the use of the seasonal influenza vaccine is highly variable around the world, making it difficult to obtain this needed real-life data. Increasing the confidence in that vaccine and knowing the data and results could increase use and eventually enable more confidence once a pandemic influenza vaccine is developed.

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

Importance of Accessible Data

Bottazzi commented on the unprecedented number of clinical trials all over the world for COVID-19 across the spectrum of vaccines, clinical care, and therapeutics but highlighted the difficulty in accessing data owned by companies or small groups. “With some data being so tightly protected, we are likely losing a lot of very important immunological information and real-life experience,” she pointed out. Balicer responded that one important issue is the infrastructure of data sharing, which carries with it several complexities from different regulatory mechanisms in different regions and the variability across them. He called for the highest level of privacy and security that is appropriate for those involved as a good basic infrastructure to assist in data sharing during an emergency—which could be tested during seasonal influenza to see how data would flow in and out. All partners should feel their data are safe and being used for the right purposes and in the right way, Balicer said. The second issue relates to incentive, because he explained that systems invest a great deal in creating and curating the data in a way that makes sense for all involved. He suggested a grant-based system that is available in an ongoing manner to create some level of certainty, so that it can kick on in an emergency and organizations will know exactly what to expect and how to prepare the data and their current data-sharing mechanisms. Finally, he noted that despite numerous trials related to COVID-19 vaccines and treatments with several thousand people, these cannot truly give a measure of the effectiveness in subgroups. This is especially true among elderly or immunosuppressed people or other populations of interest, which are critical in such an emergency. Additionally, tracking adverse events can only be assessed in a large-scale, post-emergency licensing procedure. But in this case, we do not have the flexibility of multiple years to do a gradual follow-up, he said, so these mechanisms need to be put in place in new ways. Balicer called for selecting places that are able to produce very rapid, near-real-time streams of data and compensating them so that they could be the testing ground for the world and provide needed data in real time for others to use. We need to learn from our experience in COVID-19 and make this available, he concluded.

Calls for Equity

In her initial remarks, Kaushic also emphasized the need for equity and diversity in R&D, explaining their key role in ensuring that the best research is being done and all different ideas are being brought to the table. As global investors in R&D, the funding agencies are very committed to ensuring diversity of opinions and different backgrounds are contributing

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

to the conversations, she said, so that the technologies developed are not limited to the ideas of a few.

Bottazzi recounted the early-pandemic rush of companies and stakeholders pursuing new technologies and prioritizing innovation, perhaps not realizing that the outbreak would become globally pervasive. While the world is fortunate the vaccines were proven successful and authorized so quickly, they are types that are primarily new and never licensed before, creating huge challenges in scalability, cost, and technology transfer, where more conventional methods and platforms were possible. More of a balance is needed between innovative and traditional methods so scenarios can be adapted quickly. Balicer added that when thinking about equitable distribution, the problem of logistics is often forgotten. A vaccine that requires a storage temperature of negative 80 degrees until it reaches the clinic, for example, essentially excludes a large part of the world. He suggested more focus and attention on these types of questions, including ensuring the right environment is available to maintain cold chain and other logistical requirements. Given what has been gleaned from COVID-19, he said investments should be made right now in logistics chains, freezers, and centralized data infrastructure to track vaccine movement and deployment. Another issue is how to turn large shipments into smaller boxes that can be distributed to less populated areas that may not meet a threshold for large shipments.

As a final point on equity, Balicer also highlighted the need for more emphasis on innovation in therapeutics. We have been talking about drug repurposing for at least a decade, he said, and this is the event where it should have shown beautiful outcomes, but it did not. There is still a lot of uncertainty about what actually works and what does not, he said. For too long during the pandemic, there were hints of effects of different medications and people would end up using the wrong drugs in different countries, leading to false hopes and spending scarce resources that many countries cannot afford to waste. “We need to learn from this,” Balicer exclaimed, “and in the future ensure that every country gets the right information about what works and make sure that when something really works it is available on a large scale.”

Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×

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Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
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Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
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Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
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Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
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Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
Page 23
Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
Page 24
Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
Page 25
Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
Page 26
Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
Page 27
Suggested Citation:"3 Vaccine Research and Development." National Academy of Medicine. 2022. International Workshop on COVID-19 Lessons to Inform Pandemic Influenza Response: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26352.
×
Page 28
Next: 4 Vaccine Distribution and Supply Chain »
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While the world continues to respond to the COVID-19 pandemic, novel influenza viruses persist as a constant pandemic threat. The global response to COVID-19 has pushed the boundaries on what is possible for rapid pandemic response in several areas, including vaccine research, development, manufacturing, equitable distribution, allocation, and administration. If well understood and sufficiently adapted, these actions could be applied to future pandemic and seasonal influenza vaccine preparedness efforts. However, developing and delivering these more effective vaccines to meet the demand goes beyond simply technical challenges and includes issues across governance, financing, research, supply chain, and public engagement.

To address these challenges, the National Academies of Sciences, Engineering, and Medicine convened a virtual public workshop in May of 2021 to discuss the emerging evidence on unprecedented actions related to COVID-19 that could inform and advance pandemic and seasonal influenza vaccine preparedness efforts and subsequent response. This Proceedings of a Workshop provides a high-level summary of the presentations and discussions that occurred during the workshop.

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