Emerging Infectious Diseases: Preliminary Observations on the Zika Virus Outbreak
Released: 2016-03-02T00:00:00

Letter

Background

Zika virus is a member of the flavivirus family related to dengue virus, yellow fever virus, and West Nile virus, and its primary mode of transmission is via mosquito, most notably by the Aedes aegypti mosquito. Aedes albopictus mosquitoes are a potential vector for the Zika virus. The disease was first identified in the Zika Forest in Africa in the 1940s, from which it subsequently moved eastwards over the following decades, though the Pacific Islands until it reached Brazil, where the population had no indigenous immunity against the virus. According to CDC officials with whom we spoke, the United States also has no indigenous immunity to the Zika virus.

A major factor contributing to the declaration of Zika virus disease as a Public Health Emergency of International Concern by the World Health Organization (WHO) is a possible link between Zika virus and microcephaly as well as Guillain-Barré syndrome. Microcephaly—an abnormally small head due to failure of brain growth—is a concern because children with microcephaly can experience impaired cognitive development, delayed motor function and speech, seizures, and reduced life expectancy.

To better understand the spread of this disease worldwide, epidemiological studies are required. Epidemiology is concerned with the patterns of disease occurrence in human populations and of the factors that influence these patterns. The goals of epidemiologic study, and more specifically outbreak investigations, are to determine the extent and distribution of the disease in the population, the causes and factors associated with the disease and its modes of transmission, the natural history of disease, and the basis for developing preventive strategies or interventions (see figure 1).

U.S. Role in Global Disease Surveillance

The United States has played a significant role in improving global disease surveillance and response capacity. In the mid-1990s, recognizing the threat posed by previously unknown infectious diseases, the United States and other countries initiated a broader effort to ensure that countries can detect disease outbreaks that may constitute a Public Health Emergency of International Concern. The United States has participated in the WHO’s efforts to develop and implement the International Health Regulations, currently an agreement among 196 countries, to develop and maintain global capabilities to detect and respond to disease and public health threats. The CDC has helped to define and establish the International Health Regulations and has been designated by the WHO as a key partner in helping to implement the critical capacities for detecting and responding to emerging infectious disease outbreaks.

The recent Ebola outbreak in West Africa has highlighted the importance of further improving the U.S. government’s global disease surveillance efforts. To help ensure that such threats are addressed early and at their source, the “National Health Security Strategy and Implementation Plan 2015-2018” released by the U.S. Department of Health and Human Services prioritizes efforts to strengthen national capacities and capabilities globally to detect disease in a timely manner, prevent the global spread of public health threats and diseases, and respond to public health emergencies. For example, CDC’ s Global Disease Detection and Field Epidemiology Training programs aim to strengthen laboratory systems for the rapid detection and control of emerging infectious diseases and train epidemiologists to effectively detect, investigate, and respond to health threats.

The Epidemiology and Transmission of the Zika Virus are Not Fully Understood and Accurate Information on the Incidence is Lacking

While several countries have reported outbreaks of Zika virus disease, unanswered questions remain regarding the epidemiology and the transmission of the disease. Many factors, including a large number of asymptomatic patients, mild symptoms, a lack of a consistent international case definition of Zika virus disease, as well as of microcephaly, and a lack of validated diagnostic tests complicate our understanding of the virus and may hinder our response to the current outbreak. Questions also remain regarding the strength of the association between Zika virus infection and microcephaly or Guillain-Barré syndrome.

Several Countries Have Reported Outbreak of Zika Virus Disease

Since the 1960s, the Zika virus has been known to occur within a narrow equatorial belt from Africa to Asia. In 2007, the virus was detected in Yap Island, the first report that the virus spread outside of Africa and Indonesia to Pacific Islands. In 2014, the virus spread east across the Pacific Ocean to French Polynesia, then to Easter Island. According to the WHO, the virus has continued to spread to the Americas, with the outbreak in Brazil that began in May 2015 and is ongoing. Zika has spread to Mexico, Central America, the Caribbean, and South America, where the outbreak has reached epidemic levels (see figure 2). Recent outbreaks have also been reported in Puerto Rico, as well as the Cape Verde Islands.

A Number of U.S. Travelers Have Been Infected with the Zika Virus

According to CDC documentation, Zika virus disease is now a nationally notifiable disease. As of February 24, 2016, 107 cases of continental U.S. travel-associated Zika virus disease have been reported, according to CDC. Although CDC documentation states that Zika virus has not yet seen local mosquito-borne spread in the continental United States, some states have mosquito species potentially capable of transmitting the virus.

Incidences of mosquito-borne transmission have been reported in the Commonwealth of Puerto Rico, the U.S. Virgin Islands, and American Samoa. The first locally-acquired case of Zika virus disease in Puerto Rico was reported in December of 2015. Through late January of 2016, about 30 additional laboratory-confirmed cases were identified in Puerto Rico, including one pregnant woman. In January of 2016, the CDC issued travel guidance for travel to affected countries, including the use of enhanced precautions for all travelers, as well as the recommendation that pregnant women postpone travel to affected areas.

Questions Remain about the Transmission of the Zika Virus

According to CDC documentation, there are a few known routes of transmission of the Zika virus to and among people. These include mosquitoes, mother to child, sexual contact and blood transfusions. The Zika virus is transmitted to people primarily through the bite of infected Aedes species mosquitoes (primarily Aedes aegypti and possibly Aedes albopictus). These are the same mosquitoes that spread dengue and chikungunya viruses. These mosquitoes typically lay eggs in and near standing water in containers like buckets, bowls, animal dishes, flower pots, and vases. They prefer to bite people, and live both indoors and outdoors. Mosquitoes that spread dengue, chikungunya, and Zika are aggressive daytime biters, but also bite at night. Mosquitoes can become infected when they feed on a person already infected with the virus.

According to the CDC, the Zika virus is rarely transmitted from an infected mother to child, and there have been no reports of infants contracting the Zika virus through breastfeeding. It is possible but rare that an infected mother would pass the virus to a newborn at delivery. However, an infected mother can pass the Zika virus to her fetus during pregnancy.

According to the CDC, it is possible for the Zika virus to be spread by a man to his sexual partners. A few recent cases of Zika virus transmission were reported through sexual contact. In December 2013, during a Zika virus outbreak in French Polynesia, Zika was isolated from the semen of a patient. In one known case of likely sexual transmission, the virus was spread before symptoms developed. The virus appears to be present in semen longer than in blood. Sexual transmission of the disease— acquired outside of the United States—has been reported in the United States. As of February 23, 2016, the CDC and state public health departments are investigating 14 additional reports of possible sexual transmission of the virus, including several involving pregnant women.

Zika virus can also be transmitted through blood transfusion, according to U.S. Food and Drug Administration (FDA) documents. While there have been no reports to date of Zika virus entering the U.S. blood supply, the risk of blood transmission is considered high based on the most current scientific research of how Zika virus and similar viruses (i.e. flaviviruses) are spread, as well as recent reports of transfusion-associated infection outside of the United States, according to the FDA. CDC reports that there have been reports of possible blood transfusion transmission cases in Brazil. During the French Polynesian outbreak in 2013, 2.8 percent of blood donors tested positive for Zika. The maximum time the virus remains in the bloodstream is unknown, but scientists estimate that it is less than 28 days. On February 16, 2016, as a safety measure against the emerging Zika virus outbreak, the FDA issued new guidance recommending that blood donors be deferred for four weeks if they have been to areas with active Zika virus transmission, potentially have been exposed to the virus, or have had a confirmed Zika virus infection.

While scientific studies have identified Zika viral components in saliva and urine, they did not report disease transmission from those bodily fluids.

Questions Remain Regarding the Link between Zika Virus Infection and Neurological and Auto-Immune Disorders

It is not currently known if infection with the Zika virus causes, facilitates, or is otherwise associated with the development of certain neurologic and auto-immune conditions. Although strongly suspected, a report suggests the causal relation between in-utero exposure to Zika and microcephaly is yet to be established. Scientific literature has identified several possible linkages, including the presence of Zika virus in fetal brain tissue, as well as evidence of the virus crossing the placental barrier, suggesting a causal effect is plausible, but not yet proven. For example, a fetal autopsy identified an abnormally small brain, as well physical markers of developmental delays, along with the Zika virus in the brain. The mother in the case reported an illness with a fever and rash at the end of the first trimester of pregnancy while she was living in Brazil.

A retrospective analysis was reported to the WHO in 2015-2016 of a previous outbreak of Zika virus disease in 2013-2014 in French Polynesia, also established elevated numbers of neurological disorders for that outbreak.

The potential association of Guillain-Barré syndrome and Zika virus disease was suspected prior to the recent Brazilian Zika disease outbreak. According to the European Center for Disease Control, the 2013 to 2014 French Polynesian outbreak of Zika virus disease was reportedly the largest documented outbreak at that time. According to the European Center for Disease Control, over 8,000 suspected cases of Zika Virus infection had been reported by February 2014. Notably, there were nearly 40 cases of Guillain-Barré syndrome reported, with all cases following disease episodes compatible with Zika virus infection. Historically, there had been 10 or fewer cases of Guillain-Barré syndrome in Polynesia annually. The European Center for Disease Control stated that further investigations could be conducted to establish the relationship between neurological and auto-immune complications and Zika virus infection.

Mild Symptoms and Asymptomatic Cases May Lead to Underestimation

Researchers have reported that an estimated 80 percent of the individuals infected with the Zika virus are asymptomatic, that is, they have the virus but do not manifest clinical symptoms. Since diagnosis of suspected Zika virus disease is often based on clinical symptoms, and in light of the fact that clinical symptoms are usually non-existent or mild, experts told us that many individuals who are infected with the Zika virus may not seek medical care, and thus are not counted as a case, resulting in significant underestimation of the true incidence of infection.

Lack of Consistent International Case Definitions May Lead to Inaccurate Count

An accurate count of the number of Zika virus disease cases requires a consistent case definition, or set of uniform criteria to define the disease for public health surveillance and to determine who is included in the count and who is excluded. However, establishing a definition is problematic for Zika virus disease. If Zika cases are diagnosed based on serology data, then the incidence count may include people who have been infected with the virus, but do not show clinical symptoms. On the other hand, if cases are defined by clinical symptoms only, with no serology testing, then the incidence could be higher or lower than that count obtained from serology testing only, because people who present with clinical symptoms may or may not actually test positive for Zika virus.

According to the WHO Zika Response Strategy, there is currently a need to establish a uniform case definition for Zika virus disease, as well as historical rates, or baselines, for associated conditions. The Council of State and Territorial Epidemiologists currently has a case definition for Zika virus disease—under arboviral diseases—with two tiers: a “probable case” definition based on clinical signs and symptoms as well as the presence of certain anti-Zika antibodies, and a “confirmed case” definition for laboratory-confirmed cases based on laboratory analysis. However, because other countries may be using different testing protocols, it is unclear whether their results would be consistent with the CDC case definitions, complicating epidemiological analysis. Engaging international cooperation to establish uniform case definitions and baselines for diagnosing Zika virus disease and microcephaly can facilitate discovery of modes of transmission and causal links between Zika virus disease and microcephaly or Guillain-Barré syndrome.

Lack of a Case Definition of Microcephaly May Complicate Linkage with Zika Virus Disease

When the WHO declared a Public Health Emergency of International Concern on February 1, 2016, it acknowledged that there was no international standard surveillance case definition for microcephaly. Problems with changing case definitions, lack of sufficient information on underlying causes and brain pathology, and lack of baseline data make it difficult to accurately determine the level of increase of microcephaly in Brazil, and how much is due to the Zika virus.

Some researchers offered several possible explanations for the observed increase in microcephaly cases, other than actual increase of cases as a result of Zika virus infection. First, because of the recent attention, newborn babies with visible cranial deformities are likely to be fast- tracked for in-depth examination. This temporal increase in suspected cases of microcephaly could also be distorted given both raised awareness with more children than usual being measured and reported, and the changing definition of microcephaly over time. Although there is evidence of an increased number of cases of microcephaly in Brazil, these authors demonstrated that the number of suspected cases relied on a screening test that had very low specificity and therefore overestimated the actual number of cases.

Lack of Validated Diagnostics Tests May Mask the Incidence of Zika Virus Disease

According to the CDC, there are currently two Zika diagnostic tests available in the United States: reverse transcription polymerase chain reaction (RT-PCR) and Immunoglobulin M (IgM) followed by the Plaque Reduction Neutralization Test (PRNT) test. The current RT-PCR test can detect infection only during the period of illness when the virus is present. According to an NIH official, the PRNT diagnostic test is the most specific for antibody detection, but is cumbersome and not suitable for screening a large number of individuals.

When detecting antibodies, diagnosing cases of Zika virus disease and differentiating it from other diseases caused by other flaviviruses, such as dengue or yellow fever, is difficult if someone has been infected by another flavivirus. Some tests for Zika virus antibodies suffer from cross- reactivity with antibodies to similar viruses, such as from dengue virus disease, meaning that tests using these antibodies for detection are not specific for the Zika virus. For example, a person previously infected with another flavivirus such as dengue could be falsely identified as also having been exposed to the Zika virus (and vice-versa). In addition, new outbreaks like Zika may not have known patterns or trends, making effective surveillance challenging. For example, after the onset of illness, Zika virus remains in the blood for about 5-7 days, according to the CDC. After this period, called viremia, diagnosis of Zika virus disease at this time relies on detection of antibodies against the Zika virus. Since antibodies in the blood may persist longer than the virus, a positive result for antibodies against the Zika virus indicates only that the patient was previously exposed to the Zika virus. Thus, the window for detecting the actual virus is small. It is not clear whether an antibody test could determine how long ago the patient was exposed.

According to the CDC, while there are no commercially-available diagnostic tests for Zika, an antibody-based test for the Zika virus (Zika MAC-ELISA) was recently authorized for Emergency Use by the FDA. One of the main limitations of this test, among others, is its inability to differentiate between infection with Zika and other closely related flaviviruses such as dengue. This test in its current form may confuse the practitioners because of its lack of specificity. Since closely related flaviviruses such as dengue may also be present in Zika outbreak countries, the utilization of this assay could wrongly identify non-Zika- virus associated infections, thus putting extra burden on the laboratory and health care systems, and distort the epidemiological analyses.

Adding to the limitations of these diagnostic systems are limited numbers of facilities able to perform definitive confirmatory testing, particularly in the developing world. The WHO is undertaking an analysis of diagnostics under development, developing target product profiles, facilitating the preparation and characterization of reference reagents, and setting up an Emergency Use Assessment and Listing mechanism for priority Zika diagnostics.

Various Methods of Mosquito Control Exist and Novel Approaches Are Underway

Because Zika virus disease cannot yet be prevented by drugs or vaccines, vector (mosquito) control remains a critical factor in mitigating risks associated with this disease. The Aedes aegypti and Aedes albopictus mosquitoes are present around the world, as well as in the United States. Figure 3 shows a predicted distribution and intensity of the Aedes aegypti and Aedes albopictus mosquitoes, respectively, and indicates that the southeastern United States, particularly the Gulf Coast states, could be at risk of exposure in the near future. Figure 4 shows the approximate distribution of Aedes aegypti and Aedes albopictus mosquitoes in the United States in more detail.

There are both large scale and personal methods for mosquito control. We provide a brief preliminary overview of some population-scale control methods identified in the literature, agency documents, and interviews with industry officials and academicians, which include three potentially- overlapping categories: (1) standing water treatment, (2) insecticides, and (3) emerging technologies. For some of these emerging techniques, their effectiveness remains to be demonstrated, but they have the potential to be additional tools in mosquito control. Personal methods, such as use of repellents, nets or long-sleeved clothing and staying indoors in air- conditioned locations are out the scope of this report.

Standing Water Treatment

Standing water treatment for mosquito control can be achieved by the physical reduction of bodies of water or by treating the water with chemicals that kill mosquito larvae or interfere with their development. According to CDC documentation, these treatments include use of certain bacteria or insecticides that mimic mosquito hormones, which prevents mosquitoes from maturing or kills them as larvae. Another method involves coating water with a thin film of oil to suffocate immature larvae.

Insecticide Dispersal

According to CDC documentation, insecticide dispersal relies on various techniques such as space spraying by trucks or aircraft, or residual spraying, which entails coating surfaces with insecticide. Spraying is one method currently used in the United States. CDC documentation and scientific literature have established that in the long-term, the effectiveness of spraying may be diluted due to insecticide resistance, concerns over environmental exposure, and questionable efficacy of externally-delivered wide-area fogging or spraying. Additionally, the WHO notes that reactive space spraying during emergencies has a low impact unless integrated with other control strategies. Researchers are developing new chemicals that are more targeted towards mosquitoes, and are attempting to alleviate human toxicity issues.

The use of insecticides as control methods effectively reduced mosquito- borne diseases, including malaria and yellow fever, in most of the world in the 1940s-1960s. The WHO determined that maintaining vector control after a disease subsides is complicated by dwindling resources. Indeed, by the 1980s-1990s, many dangerous vector-borne diseases re-emerged or spread to new regions.

Additionally, the spread of some diseases, such as dengue virus disease, can be attributed to a combination of mosquito, viral, and human factors. To address the resulting complexities of such disease transmissions, the WHO uses “Integrated Vector Management,” which leverages multiple control methods based on surveillance and evaluation of involved insects and disease epidemiology.

Emerging Technologies

Emerging technologies include (1) use of biological control methods, (2) genetically-modified mosquitoes, and (3) auto-dissemination traps. Based on scientific literature, these technologies show some promise in studies to overcome issues associated with use of insecticides, such as insecticide resistance. Many of these methods have been tested in smaller-scale controlled field trials internationally. We have not done an independent, comprehensive evaluation of these technologies, due to time limitations.

Biological Control Methods

Biological control methods include introducing natural predators of mosquitoes or their eggs and using bacteria to prevent disease transmission to humans. For example, certain small crustaceans and certain fish eat mosquito larvae. The suitability of this approach for the Zika virus is uncertain because the primary mosquito species identified for Zika transmission are the Aedes aegypti and Aedes albopictus, which can breed in very small volumes of water, such as those found in tin cans or in plates under potted plants.

Scientific literature has identified another approach—using bacteria to reduce disease transmission from mosquitoes to humans. This bacteria, called Wolbachia, can be transferred from mosquitoes to their eggs, thereby propagating this effect to future generations. This tactic has been demonstrated in laboratory environments and is undergoing field trials internationally, particularly in areas affected by the dengue virus.

Genetically Modified Mosquitoes

Control of the disease-transmitting mosquito population using genetically modified mosquitoes can be potentially achieved in different ways. Some genetically-modified mosquitoes are engineered with a “lethal” gene that constantly makes a protein that kills the mosquito larvae. According to one company creating these mosquitoes, the use of genetically modified mosquitoes allows for population control by introducing male genetically-modified mosquitoes that transfer this lethal gene to the female mosquito’ s eggs. As a result, mosquito larvae with the inherited lethal gene die. The company claims it has achieved a 90 percent reduction in mosquito populations using its method of releasing the modified male mosquitoes 1-3 times weekly over a period of months. The modified mosquitoes do not persist in the environment, as released mosquitoes generally die out on their own. Given the estimated 200- meter range of a male mosquito during its lifetime, scalability may be challenging. Another genetically-modified mosquito method incorporates viral resistance into mosquitoes, with the goal of replacing existing populations of mosquitoes with one less capable of disease transmission, rather than reducing the number of mosquitoes. Scientific literature indicates there may be public opposition to release of genetically-modified mosquitoes for either procedure due to uncertainties about their effect on people and the environment, or other unknown consequences.

Auto-dissemination Traps

Mosquito control by auto-dissemination traps functions similarly to insecticides, but relies on containers coated with similar chemicals. After a mosquito lands on these containers, they are contaminated with the chemicals and subsequently transfer them to the location where they lay eggs, which may result in larval death. In the case of the Aedes aegypti mosquito, WHO documentation indicates these locations tend to be small containers, so auto-dissemination is particularly suited to these mosquitoes. Auto-dissemination traps have shown 42-98 percent decreases in Aedes aegypti mosquito population in field trials.

Federal Priority Research Agenda is Ambitious and Implementation of Some Research May be Challenging

NIH and CDC have identified areas of high priority for research related to the Zika virus. In addition, the Administration’s $1.9 billion emergency funding request to combat the spread of the Zika virus is intended to provide resources to both NIH and CDC to this end. If approved, the NIH would receive $130 million to support vaccine development and other work related to Zika and other mosquito-borne diseases such as chikungunya. The CDC would receive $828 million, including $225 million for grants and technical assistance, in part to expand mosquito or vector control. The FDA would receive $10 million, in part to support the approval of new diagnostic tests and evaluation of treatment efficacy.

NIH has identified areas of high priority including:

Basic research to understand viral replication, pathogenesis, and transmission, as well as the biology of the mosquito vectors; potential interactions with co-infections such as dengue and yellow fever viruses; animal models of Zika virus infection; and novel vector control methods; and

Pursuing Zika virus research to develop sensitive, specific, and rapid clinical diagnostic tests; drug treatments for Zika virus as well as broad spectrum therapeutics that treat multiple flaviviral infection; and effective vaccines and vaccination strategies.

On February 5th, 2016, several NIH institutes issued a notice to researchers indicating NIH’ s interest in supporting research to understand transmission of the Zika virus, optimal screening and management in pregnancy, and the mechanisms by which the Zika virus affects the developing nervous system, including potential links to microcephaly. This notice was followed by a Funding Opportunity Announcement issued on February 19th, 2016, to create an expedited mechanism for funding exploratory and developmental research projects on these topics.

The CDC has identified priority areas of research focus on Zika including:

Determining the link between Zika virus infections and the birth defect microcephaly and measuring changes in incidence rates of the birth defect over time; Improving diagnostics for the Zika virus, including advanced methods to refine tests and support advanced developments for vector control; and

Enhancing international capacity for virus surveillance, expanding laboratory testing, and health care provider testing in countries at highest risk of Zika virus outbreaks.

These research activities are intended to supplement other activities for response, readiness and surveillance.

The priority research areas identified by NIH and CDC are ambitious and agencies may face some challenges in implementing this agenda, including:

Given that there are few known cases in the United States, NIH and CDC may have to rely on the cooperation of other countries with sufficient number of cases in order to carry on the proposed research. However, data from other countries may be different due to different definitions of Zika virus disease and microcephaly.

Demonstrating the link between the Zika virus and microcephaly may depend not only on the presence of the virus, but also on environmental and nutritional factors. In addition, shifting case definitions and a lack of baseline data makes it difficult to determine the increase, if any, in microcephaly and how much can be attributed to the Zika virus.

The presence of a high percentage of asymptomatic cases makes it difficult to conduct epidemiological studies, both in identifying exposed and unexposed individuals for case control studies.

Prior infection or co-infection with another virus such as dengue may complicate any analyses.

NIH officials told us that prior work on similar viruses has allowed them to make rapid progress on both a DNA-based vaccine (based on prior work on West Nile Virus), and a live attenuated virus vaccine modeled after the dengue virus vaccine that is currently in phase 3 clinical trials in Brazil. NIH officials told us that prior “platform” work on similar viruses has expedited response to the Zika outbreak, and in the development of diagnostic tests and vaccines.

With regard to the dengue vaccine, NIH provided us with the following timeline: It has taken more than 16 years, and trials are not yet complete. NIH officials told us that given their past experience with the development of vaccine for dengue fever, a vaccine for Zika could be ready for use in an emergency situation in three to four years, in the best case scenario. However, when we asked NIH about this estimate, NIH stated that the National Institute of Allergy and Infectious Diseases plans to begin a Phase I clinical trial within this calendar year. If a candidate vaccine shows promise in Phase I testing, additional clinical testing could begin by 2017 in countries where the disease is found, if the outbreak is still ongoing. The progress of these additional tests, and whether they can contribute to successful licensure, depends on a number of factors, including scientific and technical progress, as well as the size of any ongoing Zika outbreaks during clinical testing. For this reason, it is difficult to provide an exact estimate for the time it will take to develop a Zika vaccine from preclinical studies through clinical testing and licensure.

Zika virus disease poses new challenges to vaccine development and testing. This disease has specific and important implications for pregnant women. There are substantial knowledge gaps in current understanding of Zika, irrespective of the affected population. Since Zika virus disease is associated with, and may cause, adverse fetal outcomes, pregnant women are at particular risk and may benefit from measures such as vaccines. There are several current scientific and structural barriers to developing and testing vaccines for pregnant women. Overcoming these barriers may extend timeframes for vaccine testing and approval. The information we have from NIH and our prior work suggests that development of a Zika virus vaccine may take longer than anticipated by NIH.

Appendix I: Related GAO Work

Biosurveillance: Ongoing Challenges and Future Considerations for DHS Biosurveillance Efforts. GAO-16-413T. Washington, D.C.: February 11, 2016.

Air Travel and Communicable Diseases: Comprehensive Federal Plan Needed for U.S. Aviation System’s Preparedness. GAO-16-127. Washington, D.C.: December 16, 2015.

Emerging Animal Diseases: Actions Needed to Better Position USDA to Address Future Risks. GAO-16-132. Washington, D.C.: December 15, 2015.

Climate Change: HHS Could Take Further Steps to Enhance Understanding of Public Health Risks. GAO-16-122. Washington, D.C.: October 5, 2015.

Biosurveillance: Challenges and Options for the National Biosurveillance Integration Center. GAO-15-793. Washington, D.C.: September 24, 2015.

Biosurveillance: Additional Planning, Oversight, and Coordination Needed to Enhance National Capability. GAO-15-664T. Washington, D.C.: July 8, 2015.

Federal Veterinarians: Efforts Needed to Improve Workforce Planning. GAO-15-495. Washington, D.C.: May 26, 2015.

Biological Defense: DOD Has Strengthened Coordination on Medical Countermeasures but Can Improve Its Process for Threat Prioritization. GAO-14-442. Washington, D.C.: May 15, 2014.

National Preparedness: HHS Has Funded Flexible Manufacturing Activities for Medical Countermeasures, but It Is Too Soon to Assess Their Effect. GAO-14-329. Washington, D.C.: March 31, 2014.

National Preparedness: HHS Is Monitoring the Progress of Its Medical Countermeasure Efforts but Has Not Provided Previously Recommended Spending Estimates. GAO-14-90. Washington, D.C.: December 27, 2013.

Homeland Security: An Overall Strategy Is Needed to Strengthen Disease Surveillance in Livestock and Poultry. GAO-13-424. Washington, D.C.: May 21, 2013.

National Preparedness: Efforts to Address the Medical Needs of Children in a Chemical, Biological, Radiological, or Nuclear Incident. GAO-13-438. Washington, D.C.: April 30, 2013.

Influenza: Progress Made in Responding to Seasonal and Pandemic Outbreaks. GAO-13-374T. Washington, D.C.: February 13, 2013.

Homeland Security: Agriculture Inspection Program Has Made Some Improvements, but Management Challenges Persist. GAO-12-885. Washington, D.C.: September 27, 2012.

Biosurveillance: Nonfederal Capabilities Should Be Considered in Creating a National Biosurveillance Strategy. GAO-12-55. Washington, D.C.: October 31, 2011.

National Preparedness: Improvements Needed for Acquiring Medical Countermeasures to Threats from Terrorism and Other Sources. GAO-12-121. Washington, D.C: October 26, 2011.

Homeland Security: Challenges for the Food and Agriculture Sector in Responding to Potential Terrorist Attacks and Natural Disasters. GAO-11-946T. Washington, D.C.: September 13, 2011.

Homeland Security: Actions Needed to Improve Response to Potential Terrorist Attacks and Natural Disasters Affecting Food and Agriculture. GAO-11-652. Washington, D.C.: August 19, 2011.

Influenza Vaccine: Federal Investments in Alternative Technologies and Challenges to Development and Licensure. GAO-11-435. Washington, D.C.: June 27, 2011.

Influenza Pandemic: Lessons from the H1N1 Pandemic Should Be Incorporated into Future Planning. GAO-11-632. Washington, D.C: June 27, 2011.

Live Animal Imports: Agencies Need Better Collaboration to Reduce the Risk of Animal-Related Diseases. GAO-11-9. Washington, D.C.: November 8, 2010.

Biosurveillance: Efforts to Develop a National Biosurveillance Capability Need a National Strategy and a Designated Leader. GAO-10-645. Washington, D.C.: June 30, 2010.

Veterinarian Workforce: The Federal Government Lacks a Comprehensive Understanding of Its Capacity to Protect Animal and Public Health. GAO-09-424T. Washington, D.C.: February 26, 2009.

Influenza Pandemic: Sustaining Focus on the Nation’s Planning and Preparedness Efforts. GAO-09-334. Washington, D.C: February 26, 2009.

Veterinarian Workforce: Actions Are Needed to Ensure Sufficient Capacity for Protecting Public and Animal Health. GAO-09-178. Washington, D.C.: February 4, 2009.

Influenza Pandemic: HHS Needs to Continue Its Actions and Finalize Guidance for Pharmaceutical Interventions. GAO-08-671. Washington, D.C.: September 30, 2008.

Emergency Preparedness: States Are Planning for Medical Surge, but Could Benefit from Shared Guidance for Allocating Scarce Medical Resources. GAO-08-668. Washington, D.C.: June 13, 2008.

Influenza Pandemic: Efforts Underway to Address Constraints on Using Antivirals and Vaccines to Forestall a Pandemic. GAO-08-92. Washington, D.C.: December 21, 2007.

Influenza Vaccine: Issues Related to Production, Distribution, and Public Health Messages. GAO-08-27. Washington, D.C: October 31, 2007.

Global Health: U.S. Agencies Support Programs to Build Overseas Capacity for Infectious Disease Surveillance. GAO-08-138T. Washington, D.C.: October 4, 2007.

Agricultural Quarantine Inspection Program: Management Problems May Increase Vulnerability of U.S. Agriculture to Foreign Pests and Diseases. GAO-08-96T. Washington, D.C.: October 3, 2007.

Global Health: U.S. Agencies Support Programs to Build Overseas Capacity for Infectious Disease Surveillance. GAO-07-1186. Washington, D.C.: September 27, 2007.

Influenza Pandemic: DOD Combatant Commands’ Preparedness Efforts Could Benefit from More Clearly Defined Roles, Resources, and Risk Mitigation. GAO-07-696. Washington, D.C.: June 20, 2007.

Influenza Pandemic: Efforts to Forestall Onset Are Under Way; Identifying Countries at Greatest Risk Entails Challenges. GAO-07-604. Washington, D.C.: June 20, 2007.

Avian Influenza: USDA Has Taken Important Steps to Prepare for Outbreaks, but Better Planning Could Improve Response. GAO-07-652. Washington, D.C.: June 11, 2007.

Influenza Pandemic: DOD Has Taken Important Actions to Prepare, but Accountability, Funding, and Communications Need to be Clearer and Focused Departmentwide. GAO-06-1042. Washington, D.C.: September 21, 2006.

Homeland Security: Management and Coordination Problems Increase the Vulnerability of U.S. Agriculture to Foreign Pests and Disease. GAO-06-644. Washington, D.C.: May 19, 2006.

Influenza Vaccine: Shortages in 2004-05 Season Underscore Need for Better Preparation. GAO-05-984. Washington, D.C.: September 30, 2005.

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