Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis.

Vaccines are one of the most effective public health medicinal products with an excellent safety record. As vaccines are produced using biological materials, there is a need to safeguard against potential contamination with adventitious agents. Adventitious agents could be inadvertently introduced into a vaccine through starting materials used for production. Therefore, extensive testing has been recommended at specific stages of vaccine manufacture to demonstrate the absence of adventitious agents. Additionally, the incorporation of viral clearance steps in the manufacturing process can aid in reducing the risk of adventitious agent contamination. However, for live viral vaccines, aside from possible purification of the virus or vector, extensive adventitious agent clearance may not be feasible. In the event that an adventitious agent is detected in a vaccine, it is important to determine its origin, evaluate its potential for human infection and pathology, and discern which batches of vaccine may have been affected in order to take risk mitigation action. To achieve this, it is necessary to have archived samples of the vaccine and ancillary components, ideally from developmental through to current batches, as well as samples of the biological materials used in the manufacture of the vaccine, since these are the most likely sources of an adventitious agent. The need for formal guidance on such vaccine sample archiving has been recognized but not fulfilled. We summarize in this paper several prior major cases of vaccine contamination with adventitious agents and provide points for consideration on sample archiving of live recombinant viral vector vaccines for use in humans.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG).

Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed.

Utilization of surgical resources during the USNS COMFORT humanitarian mission to the Americas, June to October 2007.

In 2007, the United States Navy Ship (USNS) COMFORT (T-AH 20), a full-capability medical treatment facility, departed for Partnership for the Americas, her first large-scale humanitarian civic assistance (HCA) mission. Analysis of operational data describes surgical resource utilization. Lessons from previous military humanitarian assistance operations were helpful when placed in the cultural context of Latin America. Premission planning decisions that included time in each port and funding determined the services that were offered to host nations. Surgical, dental, immunizations, preventive medicine, and biomedical repair services had lasting impacts. COMFORT and similar hospital ships are a superior platform to combatant vessels in providing comprehensive surgical care. Medical planning is heavily dependent upon statistics. Collection of additional clinical data on subsequent HCA missions could aid future planning decisions regarding manning, equipment, supplies, and objectives.

Xenotransplantation, xenogeneic infections, biotechnology, and public health.

Xenotransplantation is the attempt to use living biological material from nonhuman animal species in humans for therapeutic purposes. Clinical trials and preclinical studies have suggested that living cells and tissue from other species have the potential to be used in humans to ameliorate disease. However, the potential for successful xenotransplantation to cure human disease is coupled with the risk that therapeutic use of living nonhuman cells in humans may also serve to introduce xenogeneic infections of unpredictable significance. Animal husbandry practices and xenotransplantation product preparation may eliminate most exogenous infectious agents prior to transplantation. However, endogenous retroviruses are present in the genomes of all mammalian cells, have an inadequately defined ability to infect human cells, and have generated public health concern. The history of xenotransplantation, the implications for public health, the global consensus on public safeguards necessary to accompany clinical trials, and the future direction of xenotransplantation are discussed in the context of public health. Mt Sinai J Med 76:435-441, 2009. (c) 2009 Mount Sinai School of Medicine.

Influenza vaccination coverage among adult solid organ transplant recipients at three health maintenance organizations, 1995-2005.

Annual immunization against influenza is recommended for solid organ transplant (SOT) recipients. We used Vaccine Safety Datalink data from 1995 to 2005 to assess influenza vaccination during the first full vaccination season (September-February) following transplant among 1800 kidney, liver, and heart transplant recipients at three health maintenance organizations. Overall, 52% of recipients were vaccinated. Older age at transplant (age 50-64 years, OR 1.81, 95% CI 1.43-2.30; age > or =65 years, OR 1.94, 95% CI 1.39-2.69), receiving vaccination in the full season pre-transplant (OR 4.54, 95% CI 3.67-5.60), and year of transplantation were significant predictors of post-transplant vaccination. Although vaccine coverage increased during study years, SOT recipients are under-immunized against influenza. Efforts to understand barriers to vaccination and increase education of physicians managing patients while awaiting and after receipt of transplant are needed.

Postexposure interventions to prevent infection with HBV, HCV, or HIV, and tetanus in people wounded during bombings and other mass casualty events--United States, 2008: recommendations of the Centers for Disease Control and Prevention and Disaster Medicine and Public Health Preparedness.

People wounded during bombings or other events resulting in mass casualties or in conjunction with the resulting emergency response may be exposed to blood, body fluids, or tissue from other injured people and thus be at risk for bloodborne infections such as hepatitis B virus, hepatitis C virus, human immunodeficiency virus, or tetanus. This report adapts existing general recommendations on the use of immunization and postexposure prophylaxis for tetanus and for occupational and nonoccupational exposures to bloodborne pathogens to the specific situation of a mass casualty event. Decisions regarding the implementation of prophylaxis are complex, and drawing parallels from existing guidelines is difficult. For any prophylactic intervention to be implemented effectively, guidance must be simple, straightforward, and logistically undemanding. Critical review during development of this guidance was provided by representatives of the National Association of County and City Health Officials, the Council of State and Territorial Epidemiologists, and representatives of the acute injury care, trauma, and emergency response medical communities participating in the Centers for Disease Control and Prevention's Terrorism Injuries: Information, Dissemination and Exchange project. There recommendations contained in this report represent the consensus of US federal public health officials and reflect the experience and input of public health officials at all levels of government and the acute injury response community.

Recommendations for postexposure interventions to prevent infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, and tetanus in persons wounded during bombings and other mass-casualty events--United States, 2008: recommendations of the Centers for Disease Control and Prevention (CDC).

This report outlines recommendations for postexposure interventions to prevent infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, and tetanus in persons wounded during bombings or other events resulting in mass casualties. Persons wounded during such events or in conjunction with the resulting emergency response might be exposed to blood, body fluids, or tissue from other injured persons and thus be at risk for bloodborne infections. This report adapts existing general recommendations on the use of immunization and postexposure prophylaxis for tetanus and for occupational and nonoccupational exposures to bloodborne pathogens to the specific situation of a mass-casualty event. Decisions regarding the implementation of prophylaxis are complex, and drawing parallels from existing guidelines is difficult. For any prophylactic intervention to be implemented effectively, guidance must be simple, straightforward, and logistically undemanding. Critical review during development of this guidance was provided by representatives of the National Association of County and City Health Officials, the Council of State and Territorial Epidemiologists, and representatives of the acute injury care, trauma and emergency response medical communities participating in CDC's Terrorism Injuries: Information, Dissemination and Exchange (TIIDE) project. The recommendations contained in this report represent the consensus of U.S. federal public health officials and reflect the experience and input of public health officials at all levels of government and the acute injury response community.

Introduction: vaccination against smallpox in the posteradication era.

The following introduction describes the context in which the national smallpox vaccination program was implemented and highlights the significance of the key policy, programmatic, or scientific challenges, observations, and lessons learned that are presented in the articles that follow within this supplement to Clinical Infectious Diseases. Although the execution of this national program posed multiple complex and varied challenges, the focus of this supplement is on vaccine-associated adverse events and vaccine safety.

Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January-October 2003.

Myocarditis was reported after smallpox vaccination in Europe and Australia, but no association had been reported with the US vaccine. We conducted surveillance to describe and determine the frequency of myocarditis and/or pericarditis (myo/pericarditis) among civilians vaccinated during the US smallpox vaccination program between January and October 2003. We developed surveillance case definitions for myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination. We identified 21 myo/pericarditis cases among 37,901 vaccinees (5.5 per 10,000); 18 (86%) were revacinees, 14 (67%) were women, and the median age was 48 years (range, 25-70 years). The median time from vaccination to onset of symptoms was 11 days (range, 2-42 days). Myo/pericarditis severity was mild, with no fatalities, although 9 patients (43%) were hospitalized. Three additional vaccinees were found to have dilated cardiomyopathy, recognized within 3 months after vaccination. We describe an association between smallpox vaccination, using the US vaccinia strain, and myo/pericarditis among civilians.

A process for sentinel case review to assess causal relationships between smallpox vaccination and adverse outcomes, 2003-2004.

The US Department of Defense requested that the Advisory Committee on Immunization Practices-Armed Forces Epidemiological Board joint Smallpox Vaccine Safety Working Group define the likelihood that smallpox vaccination played a causal role in the fatal illness of an Army reservist. Reported serious adverse events for which there was no a priori reason to discount the existence of a causal association with smallpox vaccine were reviewed to assess whether they were signals of constellations of vaccine-associated adverse events. A causal relationship between the immunization experience and the index patient's death was favored, but the implication of an individual vaccine was precluded. No new smallpox vaccine-associated clinical syndromes were identified. The data supported neutrality regarding the hypothesis that dilated cardiomyopathy was causally associated with smallpox vaccine-induced myocarditis. This review of sentinel cases augmented the ongoing safety review process and was transparent, but it shares limitations with other case-based causality-assessment methods.

Clinical and virological characterization of persistent human infection with simian foamy viruses.

Persons occupationally exposed to nonhuman primates (NHPs) can be persistently infected with simian foamy virus (SFV). The clinical significance and person-to-person transmissibility of zoonotic SFV infection is unclear. Seven SFV-infected men responded to annual structured interviews and provided whole blood, oral, and urogenital specimens for study. Wives were tested for SFV infection. Proviral DNA was consistently detected by PCR in PBMCs of infected men and inconsistently in oral or urogenital samples. SFV was infrequently cultured from their PBMCs and throat swabs. Despite this and a long period of intimate exposure (median 20 years), wives were SFV negative. Most participants reported nonspecific symptoms and diseases common to aging. However, one of two persons with mild thrombocytopenia had clinically asymptomatic nonprogressive, monoclonal natural killer cell lymphocytosis of unclear relationship to SFV. All participants worked with NHPs before 1988 using mucocutaneous protection inconsistently; 57% described percutaneous injuries involving the infecting NHP species. SFV likely transmits to humans through both percutaneous and mucocutaneous exposures to NHP body fluids. Limited follow-up has not identified SFV-associated illness and secondary transmission among humans.

Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions.

CDC and the U.S. Food and Drug Administration rely on state and local health departments, health-care providers, and the public to report the occurrence of adverse events after vaccination to the Vaccine Adverse Event Reporting System. With such data, trends can be accurately monitored, unusual occurrences of adverse events can be detected, and the safety of vaccination intervention activities can be evaluated. On January 24, 2003, the U.S. Department of Health and Human Services (DHHS) implemented a preparedness program in which smallpox (vaccinia) vaccine was administered to federal, state, and local volunteers who might be first responders during a biologic terrorism event. As part of the DHHS Smallpox Preparedness and Response Program, CDC in consultation with experts, established surveillance case definitions for adverse events after smallpox vaccination. Adverse reactions after smallpox vaccination identified during the 1960s surveillance activities were classified on the basis of clinical description and included eczema vaccinatum; fetal vaccinia; generalized vaccinia; accidental autoinoculation, nonocular; ocular vaccinia; progressive vaccinia; erythema multiforme major; postvaccinial encephalitis or encephalomyelitis; and pyogenic infection of the vaccination site. This report provides uniform criteria used for the surveillance case definition and classification for these previously recognized adverse reactions used during the DHHS Smallpox Preparedness and Response Program. Inadvertent inoculation was changed to more precisely describe this event as inadvertent autoinoculation and contact transmission, nonocular and ocular vaccinia. Pyogenic infection also was renamed superinfection of the vaccination site or regional lymph nodes. Finally, case definitions were developed for a new cardiac adverse reaction (myo/pericarditis) and for a cardiac adverse event (dilated cardiomyopathy) and are included in this report. The smallpox vaccine surveillance case definitions presented in the report can be used in future vaccination programs to ensure uniform reporting guidelines and case classification.

Adverse events associated with smallpox vaccination in the United States, January-October 2003.

CONTEXT: On January 24, 2003, the US Department of Health and Human Services (DHHS) implemented a preparedness program in which smallpox (vaccinia) vaccine was administered to federal, state, and local volunteers who might be first responders during a bioterrorism event. OBJECTIVE: To describe results from the comprehensive DHHS smallpox vaccine safety monitoring and response system. DESIGN, SETTING, AND PARTICIPANTS: Descriptive study of adverse event reports from the DHHS smallpox vaccine safety monitoring and response system received between January 24 and October 31, 2003, through the Vaccine Adverse Event Reporting System (VAERS) and the Centers for Disease Control and Prevention. A total of 37,901 volunteers in 55 jurisdictions received at least 1 dose of smallpox vaccine. MAIN OUTCOME MEASURES: Number of vaccinations administered and description of adverse events and reporting rates. RESULTS: A total of 38,885 smallpox vaccinations were administered, with a take rate of 92%. VAERS received 822 reports of adverse events following smallpox vaccination (overall reporting rate, 217 per 10,000 vaccinees). A total of 590 adverse events (72%) were reported within 14 days of vaccination. Nonserious adverse events (n = 722) included multiple signs and symptoms of mild and self-limited local reactions. One hundred adverse events (12%) were designated as serious, resulting in 85 hospitalizations, 2 permanent disabilities, 10 life-threatening illnesses, and 3 deaths. Among the serious adverse events, 21 cases were classified as myocarditis and/or pericarditis and 10 as ischemic cardiac events that were not anticipated based on historical data. Two cases of generalized vaccinia and 1 case of postvaccinial encephalitis were detected. No preventable life-threatening adverse reactions, contact transmissions, or adverse reactions that required treatment with vaccinia immune globulin were identified. Serious adverse events were more common among older revaccinees than younger first-time vaccinees. CONCLUSIONS: Rigorous smallpox vaccine safety screening, educational programs, and older vaccinees may have contributed to low rates of preventable life-threatening adverse reactions. Other rare, clinically significant, or unexpected cardiac adverse events were detected by timely review of VAERS data and intensive clinical case investigation.

Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004.

CONTEXT: Neurologic illness is an infrequent but severe adverse event associated with smallpox vaccination. The reinstatement of smallpox vaccination in the United States in response to possible bioterrorism renewed concerns about vaccine-related adverse neurologic events. OBJECTIVE: To determine rates and describe the clinical features of neurologic events associated with smallpox vaccination. DESIGN AND SETTING: We assessed reports of adverse events obtained through active case reporting and review of data reported to the Vaccine Adverse Event Reporting System among 665,000 persons vaccinated against smallpox by the Departments of Defense (n = 625,400 [corrected]) and Health and Human Services (n = 39,400 [corrected]) during the 2002-2004 US Smallpox Vaccination Program. MAIN OUTCOME MEASURE: Adverse neurologic events temporally associated with smallpox vaccination. RESULTS: Between December 16, 2002, and March 11, 2004, 214 neurologic adverse events temporally associated with smallpox vaccination were reported; 111 reports involved Department of Health and Human Services and 103 involved Department of Defense vaccinees. Fifty-four percent of these events occurred within 1 week of vaccination, and 53% were among primary vaccinees. The most common neurologic adverse event was headache (95 cases), followed by nonserious limb paresthesias (n = 17) or pain (n = 13) and dizziness or vertigo (n = 13). Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 8 seizures (including 1 death), and 3 cases of Guillain-Barré syndrome. Among these 39 events, 27 (69%) occurred in primary vaccinees and all but 2 occurred within 12 days of vaccination. CONCLUSIONS: During the 2002-2004 smallpox vaccination campaign, reported neurologic events were generally mild and self-limited, and no neurologic syndrome was identified at a rate above baseline estimates. Serious neurologic adverse events, such as postvaccinal encephalitis, Bell palsy, and Guillain-Barré syndrome, occurred in accordance with expected ranges.

Mucosal and systemic antibody responses in humans infected with simian foamy virus.

Simian foamy virus (SFV) infection and the subsequent immune response are not well characterized. Blood plasma, saliva, and urine were obtained from four humans and nine chimpanzees persistently infected with chimpanzee-type SFV for an unknown length of time. SFV-specific immunoglobulin G (IgG) antibodies, but not IgA antibodies, against the Gag and Bet proteins were detected, by Western blotting, in all sample types from infected humans and chimpanzees. Overall, chimpanzee samples had higher anti-SFV IgG titers than humans. These results provide a first comparative evaluation of SFV-specific host mucosal humoral immunity in infected humans and chimpanzees that is characterized by a predominant IgG response and a virtually absent IgA response.

Frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates.

The recognition that AIDS originated as a zoonosis heightens public health concerns associated with human infection by simian retroviruses endemic in nonhuman primates (NHPs). These retroviruses include simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus (STLV), simian type D retrovirus (SRV), and simian foamy virus (SFV). Although occasional infection with SIV, SRV, or SFV in persons occupationally exposed to NHPs has been reported, the characteristics and significance of these zoonotic infections are not fully defined. Surveillance for simian retroviruses at three research centers and two zoos identified no SIV, SRV, or STLV infection in 187 participants. However, 10 of 187 persons (5.3%) tested positive for SFV antibodies by Western blot (WB) analysis. Eight of the 10 were males, and 3 of the 10 worked at zoos. SFV integrase gene (int) and gag sequences were PCR amplified from the peripheral blood lymphocytes available from 9 of the 10 persons. Phylogenetic analysis showed SFV infection originating from chimpanzees (n = 8) and baboons (n = 1). SFV seropositivity for periods of 8 to 26 years (median, 22 years) was documented for six workers for whom archived serum samples were available, demonstrating long-standing SFV infection. All 10 persons reported general good health, and secondary transmission of SFV was not observed in three wives available for WB and PCR testing. Additional phylogenetic analysis of int and gag sequences provided the first direct evidence identifying the source chimpanzees of the SFV infection in two workers. This study documents more frequent infection with SFV than with other simian retroviruses in persons working with NHPs and provides important information on the natural history and species origin of these infections. Our data highlight the importance of studies to better define the public health implications of zoonotic SFV infections.

Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1).

B virus (Cercopithecine herpesvirus 1) is a zoonotic agent that can cause fatal encephalomyelitis in humans. The virus naturally infects macaque monkeys, resulting in disease that is similar to herpes simplex virus infection in humans. Although B virus infection generally is asymptomatic or mild in macaques, it can be fatal in humans. Previously reported cases of B virus disease in humans usually have been attributed to animal bites, scratches, or percutaneous inoculation with infected materials; however, the first fatal case of B virus infection due to mucosal splash exposure was reported in 1998. This case prompted the Centers for Disease Control and Prevention (Atlanta, Georgia) to convene a working group in 1999 to reconsider the prior recommendations for prevention and treatment of B virus exposure. The present report updates previous recommendations for the prevention, evaluation, and treatment of B virus infection in humans and considers the role of newer antiviral agents in postexposure prophylaxis.