Progress in the development of poliovirus antiviral agents and their essential role in reducing risks that threaten eradication.

Chronic prolonged excretion of vaccine-derived polioviruses by immunodeficient persons (iVDPV) presents a personal risk of poliomyelitis to the patient as well as a programmatic risk of delayed global eradication. Poliovirus antiviral drugs offer the only mitigation of these risks. Antiviral agents may also have a potential role in the management of accidental exposures and in certain outbreak scenarios. Efforts to discover and develop poliovirus antiviral agents have been ongoing in earnest since the formation in 2007 of the Poliovirus Antivirals Initiative. The most advanced antiviral, pocapavir (V-073), is a capsid inhibitor that has recently demonstrated activity in an oral poliovirus vaccine human challenge model. Additional antiviral candidates with differing mechanisms of action continue to be profiled and evaluated preclinically with the goal of having 2 antivirals available for use in combination to treat iVDPV excreters.

Progress toward laboratory containment of poliovirus after polio eradication.

BACKGROUND: The first steps (phase 1) toward laboratory containment of poliovirus after eradication are a national survey of biomedical facilities and a global inventory of such facilities retaining wild poliovirus (WPV) infectious and potentially infectious materials. METHODS: We reviewed published reports on national laboratory surveys and inventories of WPV materials from each of the 3 polio-free World Health Organization (WHO) regions (the European Region, completed in 2006; the Western Pacific Region, completed in 2008; and the Region of the Americas, completed in 2010), as well as reports on progress in polio-free countries of the remaining 3 regions (the African Region, the Eastern Mediterranean Region, and the WHO South-East Asia Region). RESULTS: Containment phase 1 activities are complete in 154 of 194 WHO Member States (79%), including all countries and areas of the polio-free regions and most polio-free countries in the remaining 3 regions. A reported 227 209 biomedical facilities were surveyed, with 532 facilities in 45 countries identified as retaining WPV-associated infectious or potentially infectious materials. CONCLUSIONS: Completion of containment phase 1 global activities is achievable within the time frame set by the Polio Eradication and Endgame Strategic Plan 2013-2018.

Epidemic Intelligence Service investigations of respiratory illness, 1946-2005.

Infectious respiratory pathogens were the suspected cause of 480 outbreaks investigated by the Centers for Disease Control and Prevention's Epidemic Intelligence Service officers during 1946-2005. All epidemic-assistance investigation reports and associated articles from scientific journals were reviewed. Investigations identified 25 different infectious respiratory pathogens including, most frequently, tuberculosis, influenza, and legionellosis. Other bacterial-, viral-, and fungal-related pathogens also were identified. Epidemic-assistance investigations were notable for first identifying Legionnaires disease and Pontiac fever, hantavirus pulmonary syndrome, and new strains of human and avian influenza, as well as emerging challenges (e.g., multidrug-resistant tuberculosis and pneumococcus). The investigations provided clinical insights into such diseases as pulmonary anthrax and identified high risks of serious respiratory illnesses for persons infected with human immunodeficiency virus, other immunocompromised persons, and persons with diabetes. They identified settings placing persons at high risk of acquiring disease, including nursing homes, prisons, homeless shelters, and hospitals. Travel also placed persons at risk. Key environmental factors related to spread of diseases and occupational risks for brucellosis and psittacosis were identified. The outbreak investigations constitute a wealth of prevention experience and provide the basis for recommendations to mitigate outbreaks and reduce future risks.

The principles and feasibility of disease eradication.

Smallpox eradication framed disease eradication as a monumental public health achievement in global health equity. The principles of disease eradication are encapsulated in a constellation of four conditions: biologic feasibility, adequate public health infrastructure, sufficient funding, and sustained political/societal will. Where the constellation exists, national eradication occurs in the absence of a global initiative. Assessing the feasibility of global eradication requires determining the constellation gaps for nations of all regions and identifying the human and financial resources to fill the gaps. The economic and humanitarian benefits of eradication have strong appeal. Global polio and guinea worm efforts are underway. Regional eradication of measles and rubella has been achieved in the Americas and other diseases have been proposed. Global decisions on disease eradication should include careful consideration of opportunity costs and prioritization of limited global health resources, with the objective of providing the most appropriate, cost-beneficial, and equitable outcome of disease control.

The role of research in viral disease eradication and elimination programs: lessons for malaria eradication.

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases--smallpox, poliomyelitis, and measles--we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios.

2009 H1N1 influenza.

Within 2 months of its discovery last spring, a novel influenza A (H1N1) virus, currently referred to as 2009 H1N1, caused the first influenza pandemic in decades. The virus has caused disproportionate disease among young people with early reports of virulence similar to that of seasonal influenza. This clinical review provides an update encompassing the virology, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of the 2009 H1N1 virus. Because information about this virus, its prevention, and treatment are rapidly evolving, readers are advised to seek additional information. We performed a literature search of PubMed using the following keywords: H1N1, influenza, vaccine, pregnancy, children, treatment, epidemiology, and review. Studies were selected for inclusion in this review on the basis of their relevance. Recent studies and articles were preferred.

Containment of polioviruses after eradication and OPV cessation: characterizing risks to improve management.

The goal of the World Health Organization is to stop routine use of oral poliovirus vaccine shortly after interruption of wild poliovirus transmission. A key component of this goal is to minimize the risk of reintroduction by destruction of polioviruses except in an absolute minimum number of facilities that serve essential functions and implement effective containment. Effective containment begins with a complete facility risk assessment. This article focuses on characterizing the risks of exposure to polioviruses from the essential vaccine production, quality control, and international reference and research facilities that remain. We consider the potential exposure pathways that might lead to a poliovirus reintroduction, including para-occupational exposures and releases to the environment, and review the literature to provide available estimates and a qualitative assessment of containment risks. Minimizing the risk of poliovirus transmission from a poliovirus facility to increasingly susceptible communities is a crucial and ongoing effort requiring understanding and actively managing the potential exposure pathways.

Post-eradication poliovirus facility-associated community risks.

Minimizing the risk of poliovirus transmission from the poliovirus facility to an increasingly susceptible community is crucial when global poliovirus transmission and OPV use stops. Community risks of exposure to wild poliovirus as well as Sabin strains are highest from facility personnel who are unknowingly contaminated or infected. Immunization with OPV or IPV prevents poliomyelitis, but neither vaccine fully inhibits silent infection of the gut. Facility environments maintained at low relative humidity (<50%) may reduce poliovirus survival and inhalation risk. Circulating antibodies reduce personnel infection risks from injection or virus entry through breaks in skin or mucous membranes. Community exposure risk through inhalation of contaminated air effluent is likely low in most modern facilities. Community risks through ingestion of liquid effluents are facility-specific and may range from high to low. This assessment of community risks, when combined with assessments of facility-specific hazards and the consequences of wild or Sabin poliovirus transmission, provides the foundation for effective risk management.

Influenza pandemic periodicity, virus recycling, and the art of risk assessment.

Influenza pandemic risk assessment is an uncertain art. The theory that influenza A virus pandemics occur every 10 to 11 years and seroarcheologic evidence of virus recycling set the stage in early 1976 for risk assessment and risk management of the Fort Dix, New Jersey, swine influenza outbreak. Additional data and passage of time proved the theory untenable. Much has been learned about influenza A virus and its natural history since 1976, but the exact conditions that lead to the emergence of a pandemic strain are still unknown. Current avian influenza events parallel those of swine influenza in 1976 but on a larger and more complex scale. Pre- and post-pandemic risk assessment and risk management are continuous but separate public health functions.

Vaccine-derived polioviruses and the endgame strategy for global polio eradication.

As the global eradication of wild poliovirus nears, the World Health Organization (WHO) is addressing challenges unprecedented in public health. The live, attenuated oral poliovirus vaccine (OPV), used for more than four decades to interrupt poliovirus transmission, and the vaccine of choice for developing countries, is genetically unstable. Reversion of the small number of substitutions conferring the attenuated phenotype frequently occurs during OPV replication in humans and is the underlying cause of the rare cases of vaccine-associated paralytic poliomyelitis (VAPP) in OPV recipients and their close contacts. Whereas VAPP has long been recognized, two other adverse events have been identified more recently: (a) long-term excretion of highly evolved vaccine-derived polioviruses (VDPVs) in persons with primary immunodeficiencies, and (b) polio outbreaks associated with circulating VDPVs in areas with low rates of OPV coverage. Developing a posteradication strategy to minimize the risks of VDPV emergence and spread has become an urgent WHO priority.

Will containment of wild poliovirus in laboratories and inactivated poliovirus vaccine production sites be effective for global certification?

The absolute laboratory containment of any virus cannot be guaranteed, but a wealth of experience indicates that effective containment of wild poliovirus materials for global certification is technically and operationally feasible. Effective containment is based on the principles of minimal wild poliovirus infectious and potentially infectious materials in laboratories; minimal risks of operations in laboratories and inactivated poliovirus vaccine production facilities; minimal susceptibility of workers to wild poliovirus infection and shedding; and minimal susceptibility of populations to wild poliovirus spread. Each principle alone is imperfect, but collectively they greatly minimize the risks of transmitting wild poliovirus from the laboratory to the community.

Polio eradication: the OPV paradox.

Routine and mass administration of oral polio vaccine (OPV) since 1961 has prevented many millions of cases of paralytic poliomyelitis. The public health value of this inexpensive and easily administered product has been extraordinary. Progress of the Global Polio Eradication Initiative has further defined the value of OPV as well as its risk through vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived polioviruses (VDPV). Although both are rare, once wild poliovirus transmission has been interrupted by OPV, the only poliomyelitis due to poliovirus will be caused by OPV. Poliovirus will be eradicated only when OPV use is discontinued. This paradox provides a major incentive for eventually stopping polio immunization or replacing OPV, but it also introduces complexity into the process of identifying safe and scientifically sound strategies for doing so. The core post eradication immunization issues include the risk/benefits of continued OPV use, the extent of OPV replacement with IPV, possible strategies for discontinuing OPV, and the potential for development and licensure of a safe and effective replacement for OPV. Formulation of an informed post eradication immunization policy requires careful evaluation of polio epidemiology, surveillance capability, vaccine availability, laboratory containment, and the risks posed by the very tool responsible for successful interruption of wild poliovirus transmission.

A public-private partnership for malaria control: lessons from the Malarone Donation Programme.

In 1996, Glaxo Wellcome offered to donate up to a million treatment courses annually of Malarone, a new antimalarial, with a view to reducing the global burden of malaria. The Malarone Donation Programme (MDP) was established the following year. Eight pilot sites were selected in Kenya and Uganda to develop and evaluate an effective, locally sustainable donation strategy that ensured controlled and appropriate use of Malarone. The pilot programme targeted individuals who had acute uncomplicated Plasmodium falciparum malaria that had not responded to first-line treatments with chloroquine or sulfadoxine-pyrimethamine. Of the 161 079 patients clinically diagnosed at the pilot sites as having malaria, 1101 (0.68%) met all the conditions for participation and received directly observed treatment with Malarone. MDP had a positive effect at the pilot sites by improving the diagnosis and management of malaria. However, the provision of Malarone as a second-line drug at the district hospital level was not an efficient and effective use of resources. The number of deaths among children and adults ineligible for MDP at the pilot sites suggested that high priority should be given to meeting the challenges of malaria treatment at the community level.

Can post-eradication laboratory containment of wild polioviruses be achieved?

The purpose of containment is to prevent reintroduction of wild polioviruses from laboratories into polio-free communities. In order to achieve global commitment to laboratory containment the rationale should be clear and compelling; the biosafety levels should be justified by the risks; and the objectives should be realistic. Absolute containment can never be assured. Questions of intentional or unintentional non-compliance can never be wholly eliminated. Effective laboratory containment is, however, a realistic goal. Prevention of virus transmission through contaminated laboratory materials is addressed by WHO standards for biosafety. The principal challenge is to prevent transmission through unrecognized infectious laboratory workers. Such transmission is possible only if the following conditions occur: infectious and potentially infectious materials carrying wild poliovirus are present in the laboratory concerned; a laboratory operation exposes a worker to poliovirus; a worker is susceptible to an infection that results in the shedding of poliovirus; and the community is susceptible to poliovirus infections. At present it is difficult to envisage the elimination of any of these conditions. However, the risks of the first three can be greatly reduced so as to create a formidable barrier against poliovirus transmission to the community. Final biosafety recommendations must await post-eradication immunization policies adopted by the international community.