PNAS – Proceedings of the National Academy of Sciences of the United States of America
(Accessed 23 August 2014)
http://www.pnas.org/content/early/

Vaccines PNAS 100th Anniversary Special Feature – Introduction
Rino Rappuoli
PNAS 2014 ; published ahead of print August 19, 2014, doi:10.1073/pnas.1413559111
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Excerpt
The special issue of the centenary of PNAS provides an opportunity to review the history of vaccines, the most exciting features of vaccine science, and to contemplate the future. The picture that emerges is intriguing: The history of vaccines confirms that vaccines have been the medical intervention with the greatest beneficial impact on human health and longevity (3). Vaccines dramatically reduced the incidence of infectious diseases that historically killed hundreds of millions, and made a substantial contribution to life expectancy that during the last century in developed countries increased from ∼47–80 y (4). During the last 30 y, improvements in our understanding of immunology and technological progress involving recombinant DNA, conjugation technology, and genomics provided vaccines against diseases, which could not be conquered by conventional vaccine technologies.

Finally, new, emerging, more powerful technologies, including rationally designed adjuvants and systems biology (4–6), raise the possibility of new and better vaccines that may allow better control of existing diseases and extend the benefits of vaccination to newly emerging infectious diseases and to noncommunicable diseases as well.
In the next few decades vaccines have the potential to continue to be the most powerful tool for advancing global health and contributing to human well-being by (i) extending the benefits of vaccination beyond childhood and especially among pregnant women and the elderly; (ii) providing tools to prevent and control emerging infections, such as pandemic influenza and HIV; (iii) preventing and controlling noncommunicable diseases, such as cancer, neurodegenerative, autoimmune, and metabolic disorders that are the leading causes of morbidity and mortality in modern society; (iv) extending the benefits of vaccination to low-income countries so that during the next two decades we can close the health and longevity gap between poor and rich countries (4, 7); and (v) controlling most of the existing, and reducing the emergence of, antibiotic-resistant bacteria (8).

The bitter truth is that although vaccines keep people healthy and save money, fewer and fewer pharmaceutical companies invest in the development of new vaccines. Rather, their investment dollars are channeled disproportionately to new drug therapies in areas such as oncology, immunology, inflammation, and cardiovascular, metabolic, and neurodegenerative diseases, for which the return on investment tends to be higher and more predictable than for vaccines….

History of vaccination
Stanley Plotkin1
Author Affiliations
Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved February 5, 2014 (received for review January 13, 2014)
Abstract
Vaccines have a history that started late in the 18th century. From the late 19th century, vaccines could be developed in the laboratory. However, in the 20th century, it became possible to develop vaccines based on immunologic markers. In the 21st century, molecular biology permits vaccine development that was not possible before.

Valuing vaccination
Till Bärnighausena,b, David E. Blooma,1, Elizabeth T. Cafiero-Fonsecaa, and Jennifer Carroll O’Briena
Author Affiliations
Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved July 18, 2014 (received for review March 20, 2014)
Abstract
Vaccination has led to remarkable health gains over the last century. However, large coverage gaps remain, which will require significant financial resources and political will to address. In recent years, a compelling line of inquiry has established the economic benefits of health, at both the individual and aggregate levels. Most existing economic evaluations of particular health interventions fail to account for this new research, leading to potentially sizable undervaluation of those interventions. In line with this new research, we set forth a framework for conceptualizing the full benefits of vaccination, including avoided medical care costs, outcome-related productivity gains, behavior-related productivity gains, community health externalities, community economic externalities, and the value of risk reduction and pure health gains. We also review literature highlighting the magnitude of these sources of benefit for different vaccinations. Finally, we outline the steps that need to be taken to implement a broad-approach economic evaluation and discuss the implications of this work for research, policy, and resource allocation for vaccine development and delivery.

Vaccines, new opportunities for a new society
Rino Rappuoli1, Mariagrazia Pizza, Giuseppe Del Giudice, and Ennio De Gregorio
Author Affiliations
Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved May 27, 2014 (received for review February 18, 2014)
Abstract
Vaccination is the most effective medical intervention ever introduced and, together with clean water and sanitation, it has eliminated a large part of the infectious diseases that once killed millions of people. A recent study concluded that since 1924 in the United States alone, vaccines have prevented 40 million cases of diphtheria, 35 million cases of measles, and a total of 103 million cases of childhood diseases. A report from the World Health Organization states that today vaccines prevent 2.5 million deaths per year: Every minute five lives are saved by vaccines worldwide. Overall, vaccines have done and continue to do an excellent job in eliminating or reducing the impact of childhood diseases. Furthermore, thanks to new technologies, vaccines now have the potential to make an enormous contribution to the health of modern society by preventing and treating not only communicable diseases in all ages, but also noncommunicable diseases such as cancer and neurodegenerative disorders. The achievement of these results requires the development of novel technologies and health economic models able to capture not only the mere cost–benefit of vaccination, but also the value of health per se.

Systems vaccinology: Probing humanity’s diverse immune systems with vaccines
Bali Pulendran1
Author Affiliations
Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved May 21, 2014 (received for review March 10, 2014)
Abstract
Homo sapiens are genetically diverse, but dramatic demographic and socioeconomic changes during the past century have created further diversification with respect to age, nutritional status, and the incidence of associated chronic inflammatory disorders and chronic infections. These shifting demographics pose new challenges for vaccination, as emerging evidence suggests that age, the metabolic state, and chronic infections can exert major influences on the immune system. Thus, a key public health challenge is learning how to reprogram suboptimal immune systems to induce effective vaccine immunity. Recent advances have applied systems biological analysis to define molecular signatures induced early after vaccination that correlate with and predict the later adaptive immune responses in humans. Such “systems vaccinology” approaches offer an integrated picture of the molecular networks driving vaccine immunity, and are beginning to yield novel insights about the immune system. Here we discuss the promise of systems vaccinology in probing humanity’s diverse immune systems, and in delineating the impact of genes, the environment, and the microbiome on protective immunity induced by vaccination. Such insights will be critical in reengineering suboptimal immune systems in immunocompromised populations.

Vaccines against poverty
Calman A. MacLennana,b,1 and Allan Saula
Author Affiliations
Edited by Inder M. Verma, The Salk Institute for Biological Studies, La Jolla, CA, and approved April 2, 2014 (received for review February 14, 2014)
Abstract
With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an exciting time for vaccines against poverty, that is, vaccines against diseases that disproportionately affect low- and middle-income countries (LMICs). The Global Burden of Disease Study 2010 has helped better understand which vaccines are most needed. In 2012, US$1.3 billion was spent on research and development for new vaccines for neglected infectious diseases. However, the majority of this went to three diseases: HIV/AIDS, malaria, and tuberculosis, and not neglected diseases. Much of it went to basic research rather than development, with an ongoing decline in funding for product development partnerships. Further investment in vaccines against diarrheal diseases, hepatitis C, and group A Streptococcus could lead to a major health impact in LMICs, along with vaccines to prevent sepsis, particularly among mothers and neonates. The Advanced Market Commitment strategy of the Global Alliance for Vaccines and Immunisation (GAVI) Alliance is helping to implement vaccines against rotavirus and pneumococcus in LMICs, and the roll out of the MenAfriVac meningococcal A vaccine in the African Meningitis Belt represents a paradigm shift in vaccines against poverty: the development of a vaccine primarily targeted at LMICs. Global health vaccine institutes and increasing capacity of vaccine manufacturers in emerging economies are helping drive forward new vaccines for LMICs. Above all, partnership is needed between those developing and manufacturing LMIC vaccines and the scientists, health care professionals, and policy makers in LMICs where such vaccines will be implemented.