Meeting ReportsVaccines

A Crisis of Public Confidence in Vaccines

See allHide authors and affiliations

Science Translational Medicine  08 Dec 2010:
Vol. 2, Issue 61, pp. 61mr1
DOI: 10.1126/scitranslmed.3001738


A meeting was held in Siena, Italy, in July 2010 to review the evidence for a decrease in public confidence in vaccines, to discuss possible reasons for this phenomenon, and to develop possible strategies to improve public confidence in vaccines. Prevention of morbidity and mortality by vaccination is one of the major public health accomplishments of the last century. Nevertheless, despite the improved safety and effectiveness of vaccines, public confidence in vaccination is decreasing. Improved methods of vaccine safety assessment have not improved public confidence. In addition, dissemination of false information on the Internet has undermined public confidence globally. Reductions in vaccine uptake or use of available vaccines can and have resulted in increased morbidity and mortality due to infectious diseases. The lack of public confidence in vaccines risks undermining the political will necessary to rapidly respond to a more severe influenza pandemic in the future. To improve the current situation, we must define both the risks and the benefits of individual vaccines so that the public can understand the rationale for vaccine recommendations. Key to regaining public trust in vaccines is a credible, consistent, and unified message developed from the private and public sectors that directly addresses public concerns. Unless an active effort is made to improve public confidence and trust in vaccination, there is a risk that gains made in combating the morbidity and mortality of infectious diseases through the use of vaccines will be lost. Loss of political will resulting from this loss of public confidence may also result in inappropriate decisions regarding the development and use of pandemic influenza vaccines for use in future pandemics, thus compromising public health.


Prevention of morbidity and mortality by vaccination is considered one of the most successful public health stories (1). Before the widespread use of vaccines in the 20th century, infectious diseases such as diphtheria, polio, pertussis, smallpox, and Haemophilus influenza type b (Hib) were a major cause of death and morbidity globally. As can be seen in Table 1 (2), the widespread use of vaccines in the developed world has prevented much of this morbidity and mortality.

Table 1

Percentage reduction in cases of disease and mortality for selected vaccine preventable diseases in the United States.

View this table:

Newer vaccines against human papillomavirus and the pneumococcus promise to extend these gains. Although the effect of vaccination in the developing world has lagged behind that of the developed world, recent efforts to eliminate this disparity promise further gains against these and other diseases (3).

When smallpox, diphtheria, polio, and measles were prevalent, public acceptance of vaccines was high. In fact, after the introduction of polio vaccine in the 1950s, millions of people stood in long lines to obtain the new polio vaccines. More recently, however, although vaccines have become safer and more effective, public anxiety regarding possible side effects of vaccination has increased, and in many cases, acceptance of vaccination has decreased. Such reductions in vaccination rates have resulted in outbreaks of disease and deaths, notably from measles (4) and pertussis (5).

Despite the broad-based global positive impact of vaccination against morbidity and mortality, there is evidence that public support for vaccination in Europe, the United States, and Japan, as well as other countries is decreasing and that antivaccine movements are becoming stronger (6). In some cases, antivaccine sentiment has resulted in major decreases in vaccine coverage and even cessation of some vaccine programs. Most recently, in some cases fueled by rumors on the Internet, this trend has accelerated. Cessation of pertussis vaccination in Sweden because of possible safety concerns led to large increases in the number of pertussis cases and many deaths (5). Similarly, decreases in measles vaccine coverage due to theoretical concerns based on faulty studies by Andrew Wakefield resulted in decreases in measles coverage and deaths (7). More recently, safety concerns regarding polio vaccination in Nigeria caused a major disruption in the global polio eradication campaign and many unnecessary cases of paralytic polio (8).

In April 2009, a pandemic strain of influenza H1N1 that was associated with high levels of morbidity and mortality especially in pregnant women was identified in Mexico (9). Because of concern that this pandemic strain would spread rapidly and cause extensive mortality, the World Health Organization (WHO) declared a pandemic alert, and vaccine manufacturers globally began an accelerated effort to develop, test, and manufacture a vaccine to protect individuals against this disease. The pandemic strain was identified in April, and vaccine became available 6 months later. In terms of development and manufacturing, this was a tremendous achievement. To conserve scarce supplies of vaccine antigens and induce a more effective immune response, many countries extensively used adjuvanted vaccines for the first time (10). However, despite the effort and the concern, public acceptance of the vaccine was low and much of the vaccine remained unused.

To help better understand why this situation occurred and how public confidence in vaccination might be improved in the future, Novartis Vaccines sponsored a conference held in July 2010 in Siena, Italy. It is the purpose of this document to summarize key points discussed at this meeting, as outlined in Tables 2 and 3 (1).

Table 2

Sessions at the meeting.

View this table:
Table 3

Key points.

View this table:

Evolving Science and Technology for New Vaccines

One workshop focused on the role of evolving science and technology in enhancing public trust in vaccination. This workshop was chaired by G. Nabel and A. von Gabain. Discussion identified several key areas where scientific advances could contribute to vaccine safety and public perception of vaccine safety. These areas included not only development of new improved vaccines, but also better means of predicting vaccine efficacy, the use of improved techniques to predict and understand adverse events, the development of better tools to evaluate individual immune responses, further improvements in manufacturing safety, and better means of educating the public regarding the science of vaccines.

Development of newer vaccines with improved safety and effectiveness profiles to replace older vaccines is not a new trend. This occurred when live measles vaccine replaced the killed vaccine and when acellular pertussis vaccines were developed to replace the reactogenic whole-cell vaccines. More recently, conjugate vaccines with improved effectiveness have replaced plain polysaccharide vaccines for Hib and the pneumococcus. Cellular influenza vaccines offer the promise of influenza vaccine production without the risk of egg antigen or bacterial contamination in the final product. In the future, this trend should continue. In fact, newer techniques for development of vaccines including reverse vaccinology promise a more logical and efficient approach to new vaccine development.

In the discussion during this workshop, it was also agreed that genomics will allow the development of new tools for characterizing immune responses to predict vaccine efficacy, including single-cell characterization of major immune subsets, characterization of the antibody response repertoire in both natural infection and after vaccination, and the use of deep sequencing and genotyping of patients for identification of immune response markers for both effectiveness and adverse events. For the latter, work could begin now on development of a program aimed at defining the genetics and pathogenic mechanisms of rare diseases sometimes observed during large vaccine trials. Efforts could begin initially on recently observed events such as Guillain-Barré syndrome or Bell’s palsy.

In terms of the assessment of individual immune responses to vaccines, it was proposed that a public-private consortium be developed to facilitate the accurate clinical immune profile tests allowing for evaluation of individual immune responses elicited by vaccines and to monitor the persistence of protective immunity throughout life. The aim should be the definition of mechanisms and correlates of protection with an eye toward informing the subject that the appropriate immune responses have been generated after vaccination. Such a panel of clinical immune diagnostic tests could assess the efficacy of primary immunization at different ages, helping to determine the best age and combinations of vaccines to administer, and provide guidance regarding the need for booster immunization. Such analysis could also help in assessing the validity of immune correlates and the duration of vaccine protection.

Finally, it was felt that new technology could be used to better analyze cell substrates and final products for contaminants and adventitious agents. This would include deep sequencing of cell lines used for vaccine production and should anticipate the discovery of unsuspected adventitious agents which would lead to further improvement of current producer lines.

Improved Methods of Vaccine Safety Assessment

Because much of the antivaccine discussion and public concern regarding vaccines revolves around vaccine safety, a workshop chaired by S. Black and P. H. Lambert was organized to address these issues. Discussion during this session began with an examination of the potential for preclinical screening of vaccine candidates with biomarkers to assess vaccine safety. It was agreed that although this was a desirable goal, it was not clear how achievable this might be in the near term. The group also discussed the changing paradigm for prelicensure studies in which there is an increasing focus on safety outcomes, including rarer outcomes that have required large prelicensure studies. The two large phase 3 studies of recently licensed rotavirus vaccines were presented as an example. However, it was also agreed that the increasing attention to assessment of rarer potential adverse effects of vaccination has required a focus on more sophisticated postmarketing assessments. These efforts have included the Vaccine Safety Datalink (VSD) (11) in the United States and the General Practice Research Database (GPRD) (12) in the United Kingdom, as well as the more recent VAESCO (13) consortium in the European Union (EU) and signal detection efforts within passive reporting systems such as the Vaccine Adverse Event Reporting System (VAERS) (14). Application of sophisticated “rapid cycle” statistical techniques now allow detection of possible adverse event signals within months of the licensure of newer vaccines. In the future, it is hoped that genomic testing will offer the ability to identify subsets of people at risk for certain adverse events and for separate management of such individuals.

Overall, it was felt that although the assessment of vaccine safety in both the pre- and the postlicensure setting has improved markedly in the past two decades, this has not resulted in improved public confidence in vaccines but rather the opposite. It was felt that public understanding of signal detection and risk benefit assessments was poor and that there was a tendency for the public to view any possible risk as making a vaccine undesirable. In the discussion of this group and that of the group chaired by Dr. Nable, it was felt that tools needed to be developed to allow access to data on the effects of vaccination, including the number of infections avoided and accurate data on adverse effects. Educational programs including not only safety and effectiveness content but also information on how to make risk benefit decisions should be developed. In particular, it was felt that it would be important to scientifically evaluate the value of educational programs and to make use of modern technology such as Twitter or Facebook to make this information widely available.

An important aspect for potential success was considered to be transparency about the current state of knowledge.

The Role of the Private and Public Sectors

It was recognized that all of these efforts would require a collaborative effort. The workshop on the role of the private and public sectors, chaired by T. Yamada and G. Atkinson, was organized to address how this might take place. This group felt that trust in immunization is a vast problem, transcending pharmaceutical companies producing vaccines or the public health agencies recommending them. It was felt that a fundamental change in the relationship between the public and the private sectors would be required to address the problem of decreasing public trust. It was felt that to increase public trust, pharmaceutical companies needed to be more transparent with the rationale for their studies, in discussing the rationale for vaccine development, and also to be more effective in communication regarding the results of studies and in their means of assessing safety and identifying any possible safety concerns. When concerns are identified, a clear program and message needs to be developed as to how this concern was identified, how it will be assessed, and what it means for the use of the vaccine in question.

The public good was felt to be ultimately the responsibility of the public sector (governments, universities, nongovernmental organizations, and others). It was felt that for specific vaccines, the public sector should be the critical partner in defining their need and use.

Vaccines for the Developing World

In the past, vaccines used in the developing world were largely limited to the basic Expanded Program on Immunization (EPI) schedule of bacillus Calmette-Guérin (BCG) for tuberculosis, DPT (diphtheria, pertussis, and tetanus), polio, and measles. In more recent years, newer vaccines such as hepatitis B, the Hib, and pneumococcal conjugates, as well as combination vaccines, have been made more accessible to the developing world. In the near future, vaccines targeted to the developing world such as malaria vaccine or a conjugate Salmonella typhi vaccine are likely to become available. This workshop was chaired by T. D. Chugh and A. Saul. The session was opened by a discussion of the burden of infectious diseases in the developing world, which put the current situation of vaccine use and vaccine need in the developing world into perspective. Infectious diseases are responsible for 23% of the global disability-adjusted life years (DALYs). However, 99% of DALYs and 96.5% of deaths due to infectious diseases are in low- and middle-income countries, of which more than 30% are caused by vaccine preventable infectious diseases (2). The key topics discussed then focused on why the available vaccines are not being used and how trust in these vaccines can be increased. Most comments indicated that a lack of government support and will was the main cause of low vaccine coverage in many countries and that the best way to overcome this is to generate public demand for vaccines. Although finance is often an important issue, it does not seem to be the critical missing component. In many developing countries, there is an overwhelming need for improved information gathering and sharing to build up public and governmental confidence. In many regions (for example, in India where ~70% of the population live in a rural setting), it is often not widely known that vaccination is a success story. New platforms are needed for health education and the demonstration of vaccine efficacy to the public and to medical personnel. For example, if education, advertising, local thought leaders and/or “local champions” could be used to spread success stories, like that of the Hib vaccination programs in Nigeria, confidence in and demand for existing and future vaccines could be greatly increased. In simple terms, if families can understand that their children are not sick less often as a result of immunization programs and if health departments have the relevant information to link decreased health costs and decreased mortality to immunization, then this will generate public demand. In turn, political will and government involvement can ensure that the often limited funding is allocated to boost the use of existing vaccines.

The other side of the problem faced in the developing world is that 62% of DALYs lost to infectious disease in all ages (70% in children less than 5 years old) are caused by diseases for which there are no vaccines (2). This point led to a discussion on how to develop and introduce new vaccines in a timely manner. In this context, the issue of regulatory constraints was highlighted, as was the negative impact that this has on implementing new vaccines. For example, when a vaccine is registered, many developing countries rely on review by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMEA) and require the presence of a local agency to license the vaccine. However, in some cases, such as the pentavalent pertussis vaccine, these agencies would not review this vaccine because they were reviewing the acellular pertussis vaccine, and the pentavalent vaccine was not a priority for the developed world. To ensure that such things do not happen in the future, training programs can be supported to enable developing countries to have the expertise, in terms of ethics committees and national regulatory agencies, that is needed to approve local vaccine trials and license new vaccines. A common thread was that local trials are important for building trust in a vaccine, especially because local factors, such as nutrition levels and the presence of other diseases, may affect vaccine efficacy. The need for local epidemiological data to support investment in new vaccines was also a key point that was raised. In addition, the importance of private-public partnerships for vaccine introduction and the need for vaccine manufacture to be sustainable in the long term was debated. Once again, the main feeling was that the onus has to be on the government. Although industry could play a greater role in advocating the benefits of immunization, companies are typically faced with accusations of conflicts of interest. So, as outlined above for existing vaccines, the public needs to apply pressure to the government to ensure the development of new vaccines.

An interesting issue that became clear with comments from Indian, African, and South American participants was that there is no “one size fits all” for developing nations in terms of vaccine development and use. It was proposed that there are three types of developing countries in terms of vaccine acceptance and coverage. Firstly, Latin American countries have relatively high trust in immunization, which could be attributed to a history of successful vaccine programs led by the Pan American Health Organization (PAHO), local vaccine production, local trials, public awareness, and active government participation. Secondly, African countries have a rising vaccine coverage, with most changes seen after the launch of Global Alliance for Vaccines and Immunisation (GAVI) in 2001, and the introduction of the African Vaccine Regulatory Forum (AVAREF) should continue to improve the situation. Thirdly, countries such as India have low vaccine coverage despite strong local manufacturing capacity. All these issues must be addressed when considering ways to build trust in immunization, and local well-targeted programs will be most beneficial.

The Role of New Vaccine Schedules

With the increasing number of vaccines that are available to prevent an increasing number of diseases, the routine vaccination schedule in many countries has become more complicated and crowded. A workshop session on possible new immunization schedules, chaired by S. Plotkin and F. Zepp, examined how future improvements in vaccine scheduling might affect public confidence. It was recognized that differences between the immunization schedules used in different countries appear to increase the general population’s misunderstanding regarding vaccines. Indeed, whereas in the United States the pandemic influenza vaccine was administered without adjuvants, in the EU countries authorities recommended influenza vaccines formulated with adjuvants exclusively. Differences were also apparent in recommended target groups. Because these differences are now apparent to informed consumers because of the Internet, it was felt that these discrepancies increased the impression that the health authorities did not exactly know which vaccine provided the best (that is, effective and safe) formulation and how these vaccines might best be used. This lesson, as well as others in the past, supports the notion that vaccination schedules should be harmonized globally whenever possible and that every decision should be justified with strong scientific rationales, and that rationale clearly communicated to the public. In addition, the complicated nature of the routine immunization schedule in most countries was felt to be a barrier in that not only the public but also many practitioners could not explain the rationale for many vaccine schedules. It was felt that newer vaccine delivery systems and especially newer adjuvants could offer the potential for fewer doses and a simpler schedule.

The Role of Regulatory Authorities in Improving Public Confidence in Vaccines

One major challenge that regulatory authorities will continue to face in the effort to establish and maintain public trust is finding the appropriate balance between facilitating innovative vaccine development on one hand and applying stringent, science-based regulatory oversight that ensures adequate safety on the other hand. A session to discuss the role of regulatory authorities was chaired by W. Egan. It was felt that efforts to open communication between regulatory authorities and the public, the strengthening of internal regulatory authority competencies, and adequate resourcing of the regulatory sciences should contribute to this goal. Finally, an acceptance by all parties that decision-making often needs to be made in the presence of uncertainty would further facilitate this effort. To illustrate this point, a quote by John Henry Cardinal Newman (1801–1890) was cited: “Nothing would be done at all if one waited until one could do it so well that no one could find fault with it.”

An informal polling of workshop attendees revealed that neither the official directives nor the criteria applied in vaccine review, particularly with regard to safety, were widely known or understood even though all of the attendees were vaccine specialists. This gap in understanding was perceived to extend to the general public and to health care providers as well. It was proposed that regulatory authorities should initiate more active public outreach programs that facilitate a greater degree of transparency in the review process and the outcomes of that process. A proactive effort to communicate with the public, including both health care providers and parent and patient groups, would likely go far in improving public trust. The dialogue should target issues and concerns that are most frequently the source of general public confusion (for example, what is meant by an acceptable risk for any particular vaccine)


Although there was a separate workshop on communication chaired by C. Ash and R. Moxon, all of the workshops at the meeting identified communication as a key issue. It was recognized that in the practice of medicine, vaccines are unique because they are given to healthy people. It was felt to be vital to reinforce the message of the value of vaccines and how successful they have been; however, it is also important to acknowledge any risks involved and to listen to the concerns of the public. Hence, candid discussions about the benefits and risks of vaccines are essential. Trust in vaccines can be built by actively communicating the strong but simple message that vaccines are the best way to protect your or your child’s health. Complex concepts such as herd immunity and role in community can also be made, but at a later point in the dialog.

It was felt that it was key to regaining public trust in vaccines that a credible, consistent, and unified message be developed from both the public and the private sectors. The message needs to be tailored according to the target group, geographical location, and prevailing social and cultural influences. A first important step is to ensure that health professionals are fully informed about the value of vaccines and that they feel capable of discussing vaccines and be able to convey consistent clear messages to their patients.

Along with governments, the vaccine industry has an important role to play in communicating the right message. The public need to know how rigorous the requirements are for licensing a vaccine, the costs involved in developing and manufacturing a vaccine, and the strong emphasis placed on safety during the development and evaluation of new vaccines. Transparency and access to data are sensitive issues in public trust that apply to both industry and government organizations.

Several challenges were identified in the battle to win the public’s trust. Dissemination of misleading scientific information by the lay press erodes confidence in science in general and vaccines in particular. Today, the Internet is one of the chief sources of misinformation, which needs to be promptly and vigorously rebutted. Proactive, provaccine groups can counter false information with networking tools such as blogs and Twitter, and resources should be made available to do so. Research into behavioral sciences, economics, and sociology is an important avenue to develop strategies and arguments to counter mistrust in vaccines. One could use tactics similar to those used by the antivaccine lobby—celebrities, gossip columns, and others. Although the message about vaccines should overall be a positive one, we also need to realistically add a “fear factor” and remind the public about the terrible devastation caused by the infectious diseases these vaccines prevent.

Scientific journals have a role to play by spreading a positive message about vaccines. Knowledge about the rigors and difficulties of the peer review processes of scientific journals have to be improved to avoid the publication of incorrect and misleading scientific data. Increasing interactions with the lay press to prevent misinterpretation of scientific data and timely responses to crises are crucial. Systematic postvaccination follow-up studies have an important role to play, and results should be made publicly available (for example, in the open access literature) and in language that the public can understand.

Finally, things will go wrong even with the best-tested vaccines because, after all, millions of people are involved. It was felt that industry, government, and academia all need to be prepared for adverse events and should be able to communicate correct information to the public in a timely manner.

Lessons from the Recent Pandemic Influenza Experience

A session was chaired by A. Monto and R. Webster to specifically assess lessons that might be learned from the recent pandemic influenza experience. The emergence in Mexico in April 2009 of an H1N1 influenza virus from swine that had a hemagglutinin antigenically and structurally closely related to the 1918 H1N1 Spanish influenza virus and was highly transmissible in humans raised alarm bells throughout the global influenza community. Despite rapid characterization of the pandemic H1N1 influenza virus as a novel reassortant with gene segments of avian, swine, and human origin and the absence of known molecular pathogenicity markers, predictions could not be made initially about the severity of disease in humans. Declaration of an influenza pandemic by the WHO fueled the expectation of severe respiratory disease by the general public and some governments. This was despite the pandemic being characterized as less than severe by the WHO at this point. Therefore, vaccines were produced with maximal urgency and, despite the failure of reverse genetics strategies to rapidly prepare high growth reassortants, the first vaccine doses were available within the expanded 6-month window. Antiviral stockpiling had been recommended to handle this window period, and it was used for prophylaxis and treatment, particularly in the United Kingdom. By the time substantial amounts of vaccines were available, two major waves of infection had already occurred (one in the Northern Hemisphere and one in the Southern Hemisphere). Summary data now make it clear that the 2009 H1N1 pandemic was no more severe than seasonal influenza, although the most at risk were young adults rather than the elderly.

Influenza vaccines to the pandemic 2009 H1N1 virus were highly sought after until after the peak of the Northern Hemisphere outbreak. The pandemic H1N1 vaccines were safely used in children and high-risk groups, including pregnant women. By the time the vaccine was widely available, the public had lost interest in taking another influenza “shot” against a generally mild disease. The public in the United States and most developed countries quickly became apathetic about receiving vaccine, and issues were raised about the safety of vaccines and adjuvants. Because of the low severity of the outbreak, there was increasing skepticism among the public of the need for influenza vaccine and a growing distrust of the information about influenza pandemics and the lack of severity. This distrust morphed into questions about the influence of industry on scientists who advised the WHO about declaring pandemics. The possibility was raised that any relationship between scientists and industry influence the advice given to WHO on declaring a pandemic, which resulted in recommendations for the need for vaccines with substantial profits for industry. Those “conspiracy theories” have serious implications and were raised by one of the leading medical journals as “a fake pandemic that is a threat to public health.” The misperception of influence must be clarified and the process must be made fully transparent. The influenza surveillance program under the auspices of the WHO [currently called Global Influenza Surveillance Network (GISN)] has been one of the great success stories of global public health. Fully transparent interactions between scientists, the WHO, and industry are essential for the continued success of the GISN program. The difficulty that has arisen comes from lack of knowledge. Although the genomics of the H1N1 2009 virus were rapidly established, this information did not permit forecasting of pandemic severity. Only after the characteristics of the disease severity became clear was it possible to say that the pandemic was likely to be less than severe, but uncertainty required appropriate response. It was the opinion of the working group that improvements need to be made in the future to our approach to possible pandemics. These are summarized in Table 4.

Table 4

Improvements needed in our approach to pandemic control.

View this table:

Much of the confusion about influenza pandemics and severity arises from lack of fundamental knowledge of the interplay between the virus and the host. The future understanding of the genomics of influenza viruses on host range transmission and interplay between the virus and the human host will lead to better ability to predict disease severity. Ultimately the need is the ability to produce genomic vaccines that are safe and effective and can be produced before the pandemic spreads and are available to the entire global community.


In the 20th century, vast progress was made in the prevention of morbidity and mortality from infectious diseases largely through the development and widespread use of vaccines. With eradication of these diseases, public demand for and confidence in vaccines has decreased, and many people are complacent about receiving vaccines that their grandparents stood in line to receive. Availability of misinformation on the Internet and the willingness of individuals and the press to foster misinformation have undermined the public health and in many situations have allowed the return of diseases once thought to be under control. Although new technology offers the promise of better and safer vaccines, as well as a better understanding of how vaccines work and might cause adverse events, the consensus of the meeting was that at this point communication was the key issue. Despite the availability of increasingly large and sophisticated vaccine safety assessment methods, the inability of scientists to explain the process and the results have decreased rather than improved public confidence. Scientists, public health officials, and manufacturers need to develop clear messages and transparent means of presenting data on both risk and benefit to the public. The public in turn needs to be better educated as to how to make appropriate risk benefit decisions for themselves, their children, and the communities in which they live. To not take action now to improve public confidence in vaccines will risk seeing the return of the infectious disease scourges of the past and also may lead to inappropriate decisions by policy-makers and politicians regarding future life-threatening pandemics. The issues have been identified and it was felt that the time to begin the work of improving public confidence in vaccines is now.


  • Citation: S. Black, R. Rappuoli, A Crisis of Public Confidence in Vaccines. Sci. Transl. Med. 2, 61mr1 (2010).

References and Notes

  1. Acknowledgments: We thank F. Bagnoli, D. Maione, I. Margarit, N. Nair, M. Nissum, T. Perkins, K. Seib, and M. Unnikrishman for sharing their meeting notes and considerations.
View Abstract

Navigate This Article