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Vaccines--often lauded as one of the greatest public health interventions--are losing public confidence. Some vaccine experts have referred to this decline in confidence as a crisis. We discuss some of the characteristics of the changing global environment that are contributing to increased public questioning of vaccines, and outline some of the specific determinants of public trust. Public decision making related to vaccine acceptance is neither driven by scientific nor economic evidence alone, but is also driven by a mix of psychological, sociocultural, and political factors, all of which need to be understood and taken into account by policy and other decision makers. Public trust in vaccines is highly variable and building trust depends on understanding perceptions of vaccines and vaccine risks, historical experiences, religious or political affiliations, and socioeconomic status. Although provision of accurate, scientifically based evidence on the risk-benefit ratios of vaccines is crucial, it is not enough to redress the gap between current levels of public confidence in vaccines and levels of trust needed to ensure adequate and sustained vaccine coverage. We call for more research not just on individual determinants of public trust, but on what mix of factors are most likely to sustain public trust. The vaccine community demands rigorous evidence on vaccine efficacy and safety and technical and operational feasibility when introducing a new vaccine, but has been negligent in demanding equally rigorous research to understand the psychological, social, and political factors that affect public trust in vaccines.

After exposure, human rabies is preventable by prompt application of post-exposure prophylaxis. Historically, the total number of rabies vaccine doses administered during human prophylaxis has decreased, as modern biologics have improved and scientific knowledge has grown. A review of the literature on rabies virus pathogenesis, experimental animal studies, clinical trials, epidemiological surveillance, and economic analyses was conducted to determine the potential utility of reducing the current 5-dose intramuscular series of human rabies vaccine administered in the United States. Based upon the available evidence, a reduced schedule of cell-culture rabies vaccine, administered on days 0, 3, 7, and 14, given in conjunction with rabies immune globulin, was supported and recommended by the United States Advisory Committee on Immunization Practices.

This study explored health officials' perception of parental concern regarding the safety of combination vaccines and its impact on policy decisions in different European countries. Interviews were conducted with governmental and nongovernmental health officials in the United Kingdom, France, Ireland and Sweden over a four-month period. Parental concern regarding the safety of combination vaccines was perceived to be prevalent in the United Kingdom, Ireland and Sweden while no such concern was evident in France. The concern was limited to the combined measles, mumps and rubella vaccine and its alleged causal association with autism and did not carry over to other combined vaccines. Although proposed by certain political groups, no policy changes regarding combination vaccines were made in any study country.

To describe the progress and challenges in achieving measles elimination in Canada, we analyzed national data on measles cases for 1998-2001. To assess the status of measles elimination in Canada, we estimated the effective reproductive number, R. Measles elimination was defined as the interruption of endemic transmission and failure to reestablish endemic transmission after importation. Twelve isolated cases, 29 cases (72.4% were linked to 2 outbreaks), 199 cases (96.9% were linked to 4 outbreaks of 2, 6, 30, and 155 cases), and 34 cases (73.5% were linked to 8 outbreaks of 2, 2, 2, 2, 3, 3, 3, and 8 cases) were reported in 1998, 1999, 2000, and 2001, respectively. R ranged from 0.58 to 0.95. Multiple chains of transmission occurred in religious communities that actively oppose or resist immunization efforts. Epidemiological and virological evidence suggests that endemic transmission of measles has been mostly interrupted since 1998.

An accurate system of identifying and classifying suspected measles cases is critical for the measles surveillance system in the United States. To examine the performance of the clinical case definition in predicting laboratory confirmation of suspected cases of measles, we reviewed 4 studies conducted between 1981 and 1994. A clinical case definition was examined that included a generalized maculopapular rash, fever (>or=38.3 degrees C, if measured), and either a cough, coryza, or conjunctivitis. Serological confirmation of measles was done either by hemagglutination inhibition assay, complement fixation assay, or enzyme immunoassays. The positive predictive value of the clinical case definition decreased from 74% to 1% as incidence decreased from 171 cases/100000 population to 1.3 cases/100000 population. Sensitivity was high, and for the larger studies with the most precise estimates, sensitivity was 76%-88%. The low positive predictive value of the clinical case definition in settings of low incidence demonstrates that serological confirmation is essential to ensure an accurate diagnosis of measles when measles is rare.

On 16-17 March 2000, the National Immunization Program of the Centers for Disease Control and Prevention convened 12 consultants and 10 resource specialists to review the present status of measles in the United States and to provide individual opinions on 4 questions: Is measles currently endemic in the United States? If current information is not sufficient to make such a determination, what additional information is needed? Is it possible or desirable to establish a precise definition of " elimination"? What elements of the US immunization program should be modified or strengthened to achieve/maintain elimination? The consultants and resource specialists are listed after the text. The meeting included a series of presentations, contained in this supplement issue of The Journal of Infectious Diseases, followed by open discussion among the consultants and delivery of their opinions.

Vaccines against childhood diseases represent some of the most important applications of 20th-century pediatric research. This survey examines how the components of the current U.S. immunization schedule emerged in three phases during the course of the century. The first phase, after the development of bacterial culture techniques, witnessed numerous efforts in the early 1900s to develop bacterial vaccines. It proved most fruitful with respect to diphtheria, tetanus, and pertussis. The rise of viral tissue culture techniques in the 1950s brought about a second phase of innovation resulting in vaccines against polio, measles, mumps, rubella, and varicella. A third wave of innovation, still very much alive, has drawn on a variety of new technologies and led to vaccines against hepatitis B, Haemophilus influenzae type b, pneumococcus, and still other organisms. Although basic science research has thus been a primary factor shaping the history of vaccine development, the collaboration between the academic, private, and public sectors critical to its application has not always proceeded smoothly. The history of vaccine research and development has important implications for today, as a variety of factors threaten to fragment this network.

Despite achieving and sustaining global measles vaccination coverage of about 80% over the past decade, worldwide measles remains the fifth leading cause of mortality among children aged

Increased societal concern regarding the safety of vaccines has had an impact on the risk tolerance of public health officials, parents, and medical professionals. Risks that were either unknown or accepted for years have come under new scrutiny and may result in new and changed perspectives. This has been due partly to the fact that effective immunization programs have markedly diminished the incidence of vaccine-preventable diseases in industrialized countries. As a result, there is a lower awareness of the risks associated with the diseases themselves and a greater prominence of the potential risks of adverse effects associated with the vaccines. Risk perceptions and the actions taken in response to real or perceived risks regarding vaccines can and do vary significantly among nations. Due to the heightened awareness and concern over vaccine safety issues, immunization policymakers must carefully balance newly identified potential risks from vaccines with the actual risk of vaccine-preventable diseases. Concern regarding public reactions to new and often unverified safety issues may place pressure on policymakers and/or health care providers to act quickly in response to new

A second dose of varicella vaccine is routinely recommended. We report 2 cases of large local reactions after receipt of a second dose of varicella vaccine administered in the thigh. The reactions resolved with symptomatic therapy. Clinicians should continue to administer the second dose of varicella vaccine, but should use the preferred site in the arm.

9,10 The use of IPV in combination with OPV in infants could help close the immunity gap in this critically important age cohort, and tip the balance to eliminate wild poliovirus circulation. The initial reasons for the choice of OPV were its low cost, ease of administration, and its ability to induce herd immunity by person-to-person transfer. Data from developed countries suggest that IPV also has a herd eff ect, resulting from decreased transmission of wild virus to unvaccinated individuals when some of the population is immunised. Further studies are needed to determine how well IPV can reduce transmission in tropical settings and to assess its ability to stop wild poliovirus transmission and control outbreaks in the post-eradication era. Although OPV has been the mainstay of the eradication programme, its continued use is ironically incompatible with the eradication of paralytic disease. Neurovirulent vaccine-derived polioviruses (VDPVs) generated by reversion or recombination of OPV strains can circulate in poorly immunised populations and cause outbreaks of paralytic disease.

Study objectives were to evaluate the safety and immunogenicity of three HIV recombinant glycoproteins in HIV-infected infants and children between 1 month and 18 years of age with asymptomatic (P-1) infection. Using Chiron rgp 120 (SF-2) 15 or 50 microg; MicroGeneSys rgp 160 (IIIB) 40 or 320 microg; Genentech rgp120 (MN) 75 or 300 microg; or adjuvant control (Alum or MF-59), children were randomized to a double-blind, placebo-controlled, dose-escalating study of vaccine administered intramuscularly at entry and 1, 2, 3, 4, and 6 months later. No adverse events were attributed to study vaccines. Between 30% and 56% of volunteers exhibited a lymphoproliferative response as defined in terms of stimulation index (SI) to vaccine antigens; 65% of vaccinees but none of placebo recipients exhibited moderate or strong responses after enzyme immunoassay to HIV specific antigens. CD4 cell counts and quantitative HIV culture did not differ significantly among vaccine and control groups, nor were differences found among groups in HIV disease progression. The rgp160 and gp120 subunit vaccines were safe and immunogenic in this population.

Advances in medical biotechnology mean that vaccines to prevent more than 75 infectious diseases are being or have been developed. Vaccination is unfortunately not reliant purely on biotechnology but also on politics and resources. Countries with the greatest demand for vaccines have the least ability to pay for or produce them. Health-care Infrastructure and diagnostic facilities also hamper immunisation projects in developing countries. Charitable organisations are relied on heavily to support such projects but the challenge to ensure all infants are immunised against the most common infections of childhood is still enormous. Difficulties that present themselves now should not prevent us looking into future possibilities such as immunisation during pregnancy and targeting of children for immunisation against sexually transmitted diseases. Other avenues for research are in administration of vaccines. A move to mucosal immunisation rather than use of the syringe and needle would be positive both economically and from the point of view of risk of needle contamination. Plant science may also provide a new vehicle for vaccines by engineering plants such as the banana tree to be naturally bioencapsulated vaccines. Prospects for control and eradication of infectious disease in the next century are certainly good.

We evaluated the responses of HIV-infected children to a single dose of split-virus influenza vaccine and the relationship to viral load and other characteristics.Fifty-three HIV-infected children ages 1.8 to 13.2 years were given influenza vaccine for the 1994 to 1995 influenza season (Wyeth-Ayerst: A/Texas H1N1, A/Shangdong H3N2 and B/Panama). Immunologic and virologic factors were assessed at the time of and 2 to 10 weeks after immunization.The differences between pre- and postimmunization CD4+ counts, CD4+:CD8+ ratios and viral load were not significant. Thirty-one of 53 children (58.4%) had a2-fold increase and 16 of 53 (30%) had a 4-fold rise in their postimmunization antibody titers for at least one component of the vaccine. Influenza immunization in the 1993 to 1994 flu season and administration of intravenous immunoglobulin around the time of immunization was not associated with immune response to the vaccine. Factors that were negatively associated with antibody response included increased time between samples (P = 0.004) and decreased preimmunization CD4+:CD8+ ratio (P = 0.02).Influenza immunization in this population is safe, and a positive antibody response to influenza immunization is not associated with significant clinical events or change in HIV-1 plasma viral burden.

Salk and Sabin raced along divergent pathways to develop vaccines that would be safe and effective in humans. Dr. Samuel L. Katz recounts that the two scientists were treated quite differently by their colleagues and by the public.

Although Rhazes, a Persian physician, is credited with the first written ­description of the measles [1], and perhaps with distinguishing between it and smallpox, earlier Hebrew physicians (such as Al Yehudi) had recognized the illness, but without distinction between it and other rash disorders. As urbanization occurred in subsequent centuries, the proximity or larger populations nurtured epidemics with continued circulation of virus in cities. By the seventeenth century, measles was more clearly recognized as a distinct entity as described in 1670 by the London physician, Thomas Sydenham [2]. In 1758, nearly 40 years before Jenner’s description of smallpox vaccine, a Scottish physician, Francis Home, attempted to produce mild measles by mimicking the variolation process used to mitigate smallpox [3]. Because, in contrast to smallpox, there were no vesicles or pustules, he chose to inoculate blood from an infected patient and was able to successfully pass infection with rash to ten of his 12 childhood subjects. Thus, he demonstrated the presence of viremia more than a century before the concept of virus had even been set forth.

In 1954, John F Enders, Frederick C Robbins and Thomas H Weller received the Nobel Prize in Physiology and Medicine for their successful propagation of poliovirus in tissue culture. Like many great scientific advances, this was the culmination of a lengthy series of laboratory investigations that had begun more that 20 years previously and had included the work of a great number of scientists. The publication by the Enders’ group in 1949 of their seminal work provided the “Rosetta Stone” that integrated the results of previous research and added those techniques necessary to its final completion and widespread applicability [1].

About two fifths of two-year-old children in the United States have not received recommended immunizations on schedule1. These children, and a smaller number of older children, are susceptible to p...

The authors reviewed the means by which human immunodeficiency virus (HIV) seropositivity was acquired for the 134 seropositive children seen at Duke University Medical Center prior to September 1990. Perinatal transmission occurred in 111 (83%) and blood product transmission in 15 (11%). Of the 108 mothers (there were three sets of siblings) responsible for perinatal transmission, 44 (41%) had acquired their infection while residing in North Carolina. Intravenous (IV) drug use by the mother or her sexual partner was the significant risk factor for maternal infection in 91 (84%) of the total cases and in 38 (86%) of the 44 women infected in North Carolina. The proportion of women who acquired their HIV infection from a sexual partner who was an IV drug user was significantly greater for mothers who were resident in North Carolina when infected compared with mothers infected elsewhere (P < .001). On the basis of admissions to drug treatment programs during the 1990 fiscal year, cocaine is the predominant IV drug used in North Carolina. Admissions to cocaine abuse programs occurred throughout the state, and mothers who acquired HIV infection from IV drug use were more likely to live in counties with a higher frequency of cocaine abuse treatment.

Following the landmark discovery of the Enders lab that led directly to the successful development and deployment of polio vaccines, investigators turned their attention to addressing the other, common viral diseases of childhood. Over the next two decades, these efforts would yield vaccine dividends against three of the most important causes of viral disease and would dramatically and favorably alter the global landscape of infectious diseases.

Following their initial isolation in cell culture of the virus in 1954, a succession of investigators under the mentorship of John F. Enders conducted the research, development, and initial clinical studies responsible for the licensure in 1963 of a successful live attenuated measles virus vaccine. Propagation of the virus successively in human kidney cells, human amnion cells, embryonated hens' eggs, and finally chick embryo cell cultures had selected virus that when inoculated into susceptible monkeys proved immunogenic without viremia or overt disease, in contrast to the early kidney cell-passaged material, which in similar monkeys pro- duced viremia with illness mimicking human measles. Careful clinical studies in children by the Enders group and then by collaborating investigators in many sites established its safety, immunogenicity, and efficacy. This Edmonston strain measles virus became the progenitor of vaccines prepared, studied, and utilized throughout the United States and many other countries. With appreciation of measles morbid- ity and mortality, most marked among infants and children in the resource-limited lands, the vaccine was incorporated into the World Health Organization's (WHO) Expanded Programme of Immunization (EPI) in 1974 along with BCG, OPV, and DTP. Successful efforts to further reduce measles' burden were launched in 2001 and are continuing as the Measles Initiative (Partnership) under the leadership of the American Red Cross, International Red Cross, and Red Crescent societies, Centers for Disease Control (CDC), United Nations Children's Fund (UNICEF), WHO, and the United Nations Foundation.

Public trust in the safety and efficacy of vaccines is one key to the remarkable success of immunization programs within the United States and globally. Allegations of harm from vaccination have raised parental, political, and clinical anxiety to a level that now threatens the ability of children to receive timely, full immunization. Multiple factors have contributed to current concerns, including the interdependent issues of an evolving communications environment and shortfalls in structure and resources that constrain research on immunization safety (immunization-safety science). Prompt attention by public health leadership to spreading concern about the safety of immunization is essential for protecting deserved public trust in immunization.

The attenuation of varicella-zoster virus (VZV) by Takahashi in 1974 was a remarkable achievement. It swiftly led to development of a live vaccine against chickenpox, which was initially tested in Japan. With its successful employment in immunocompromised children to prevent morbidity and mortality due to varicella, the vaccine began to be tested in healthy children in Japan and elsewhere. In the United States, vaccine use progressed from extensive clinical trials that demonstrated safety and efficacy to universal immunization of healthy infants and children. In the past 10 years, >30 million healthy American individuals, mostly children, have been vaccinated. With increasing use of vaccine, there has been a concomitant decrease in the incidence of disease, along with decreases in hospitalizations and deaths due to VZV. To improve protection, however, a 2-dose schedule of immunization was recommended for routine use in all children by the Centers for Disease Control and Prevention in June 2006. At roughly the same time, licensure of the combined measles-mumps-rubella-varicella vaccine was completed, which allowed harmonization of immunization against these 4 viruses with 1 injection given twice in childhood. Concomitantly, a version of the varicella vaccine with 10 times the titer was developed for immunization of healthy individuals >60 years of age against herpes zoster (HZ). Although elimination of VZV from human populations may not yet be possible, the combined approach of immunization against both varicella in childhood and HZ in adulthood in the developed world are predicted to dramatically increase our control of this troublesome virus.

Infants 1 to 3 months of age were immunized with a vaccine combining diphtheria and tetanus toxoids with pertussis organisms. The combination product was adjuvanted with alum. Infants were injected at four-week intervals between 1–3 months of age and boosted at 7–9 months of age. Serum antibody determinations were done 3 months after completion of the initial three administrations; again at 7–9 months of age, 6 months after completion of the original course; and a booster injection was given and final determinations obtained on serum collected at eight to ten months of age. Utilizing a variety of antitoxin and agglutination techniques, more than 90% of infants had effective antitoxin levels against diphtheria and tetanus on all three laboratory determinations whereas only 53% at 3 months, 51% at 6 months and 80% at 10 months had titers judged protective vs pertussis. It was therefore demonstrated that infants at this young age could respond satisfactorily with humoral antibodies against both diphtheria and tetanus toxoids but less so against pertussis.

The continued progress of the Polio Eradication Program has encountered a number of hurdles in the past 2 years as virus has spread from northern Nigeria across much of central Africa and into the Middle East and as far as Indonesia. India continues to be a source of virus exportation but to a much less degree. WHO is optimistic regarding elimination of circulating virus from all of these countries in 2006 with the exception of Nigeria. Newly recognized obstacles to the eradication are the circulating vaccine-derived polioviruses (cVDPV) and those originating from immune deficient patients (iVDPV). Data are presented on the numbers and locations of cases of paralytic polio in 2004 and 2005 as reported to the WHO in early 2006. Scenarios for the maintenance of freedom from polio when/if the final cases occur are considered.

* Abbreviations: AAP — : American Academy of Pediatrics FDA — : Food and Drug Administration TCV — : thimerosal-containing vaccine USPHS — : US Public Health Service A draft treaty under consideration by the United Nations Environmental Program has been prepared to greatly reduce global health hazards from environmental mercury.1 In response to the draft treaty, the World Health Organization urges removal of a provision in the treaty that calls for a ban on thimerosal (which contains ethyl mercury) in vaccines, a position recently endorsed by the American Academy of Pediatrics (AAP) and the US Public Health Service (USPHS). Removal of the ban on thimerosal-containing vaccines (TCVs) represents a significant reversal of the position expressed in an AAP/USPHS joint statement in 1999 that called for elimination of mercury in vaccines and the subsequent actions taken in the United States.2 Understanding the circumstances that led 14 years ago to the 1999 statement and the knowledge accumulated in these subsequent years can reinforce the importance of the 2012 AAP/USPHS position. AAP representatives and other members of national pediatric societies within the International Pediatric Association advocating for deletion of the provision banning TCVs need to know why the elimination of thimerosal was initially called for in 1999 but is no longer indicated. This commentary … Correspondence to Louis Z. Cooper, MD, 80 Central Park W, Apt 11F, New York, NY 10023. E-mail: lzcooper{at}verizon.net

Paralytic poliomyelitis was once endemic in the United States; however, because of high vaccination levels, the last case of wild disease occurred in 1979. Although worldwide polio eradication may be achieved in the near future, the presence of undervaccinated children in urban areas and among groups who refuse vaccination creates an outbreak risk, should importation of wild virus occur. In 1999, the Advisory Committee on Immunization Practices (ACIP) recommended that inactivated poliovirus vaccine (IPV) be used for routine immunization of the US population and that oral poliovirus vaccine (OPV) be reserved for "mass vaccination campaigns to control outbreaks of paralytic polio." Subsequently, the sole US manufacturer of OPV withdrew from the market. In 2003, a joint National Vaccine Advisory Committee (NVAC)/ACIP working group was charged with reporting to its parent bodies concerning the need for a poliovirus vaccine stockpile. Based on that working group's report, the NVAC and ACIP have concluded that stockpiles of both IPV and OPV should be maintained. In the event of an outbreak in which OPV continues not to be available, IPV should be used for control, and a stockpile of 8 million doses seems to be sufficient. Should IPV be manufactured only in combination with other vaccines, appropriate procurement actions should be taken to ensure that uncombined IPV continues to be stockpiled. Under circumstances of diminished population immunity, OPV may offer outbreak control advantages. The NVAC and ACIP recommend that the United States collaborate with international agencies to provide guaranteed and rapid access to at least 8 million doses of trivalent OPV or 8 million doses of each of the 3 types of monovalent OPV. The regulatory and practical obstacles to implementation of this recommendation will require assertive facilitation at high levels of the federal government and careful planning at the state and local levels.

This study explored the safety concerns associated with combination vaccines in Japan. The impact of Japan's decision in 1975 to withdraw the combined diptheria, tetanus, and pertussis (DTP) vaccine, and then in 1993, the combined measles, mumps, and rubella (MMR) vaccine and provide only the single antigen vaccines was analyzed. Interviews with both governmental and non-governmental agency officials in Japan demonstrated that withdrawal of the DTP and MMR vaccines had significant impact on the rates of immunization and disease despite the availability of monovalent vaccines.

Effective immunization programs have markedly diminished the incidence of vaccine-preventable diseases. As a result, there now exists in society a lower awareness of the actual risks associated with the diseases themselves and a greater prominence of the potential risks of adverse effects associated with vaccines. Concern regarding public reactions to new vaccine safety issues may place pressure on policymakers and/or health care providers to act quickly in response to new information. However, this concern must be tempered by the necessary caution required to assess the intended and unintended risks and benefits of any action undertaken. The interplay of these potentially competing demands is well illustrated by the recent safety concern involving the use of thimerosal in vaccines. Thimerosal is a mercury-containing compound that has been widely used as an antimicrobial agent in vaccines for over 60 years. Human exposure to mercury may have potentially significant health consequences. By mid-1999, the Food and Drug Administration (FDA) had discovered that children could be exposed to an amount of mercury from vaccines that exceeded 1 of 3 existing federal safety thresholds. After this realization, the organized medical and public health communities in the United States became involved in a series of urgent and intense discussions to determine an appropriate response to the issue. This manuscript describes and analyzes the process that led to the July 7, 1999, joint American Academy of Pediatrics (AAP)/US Public Health Service (PHS) statement on thimerosal,1 with the goal of suggesting improvements for managing similar vaccine safety concerns in the future. We conducted structured interviews with over 15 individuals involved in the discussions and negotiations leading to the joint AAP/PHS statement on thimerosal. The individuals represented both the governmental agencies and nongovernmental organizations involved, including the FDA, the Environmental Protection Agency (EPA), the Centers for Disease Control and …

Scott et al. have investigated an important and challenging aspect of the continuingly increasing efforts to reduce global measles-associated morbidity and mortality. What are the factors that may accelerate receptivity to attenuated measles virus vaccine by HIV-infected infants and thereby reduce their early susceptibility to "wild-type" measles virus? In early 2001 the American Red Cross initiated a program that developed a collaboration of the International Red Cross and Red Crescents the World Health Organization the United Nations Childrens Fund the United Nations Foundation the Centers for Disease Control and Prevention and later the Church of Latter Day Saints the Canadian International Development Agency and the Gates Foundation. As Rotary International had accepted the challenge of global polio eradication the Red Cross chose to focus on measles. Before a vaccine was available the World Health Organization estimated that nearly 8 million children died each year as a result ofmeasles and its complications. Although a vaccine had been available for 38 years when the Red Cross program was launched in early 2001 it was estimated that there were still nearly 900000 measles-associated deaths annually. The initial goal of this consortium now identified as the Measles Initiative or Measles Partnership was to reduce measles-associated mortality by 50% by 2005. Indeed the consortium exceeded their goal with the vaccination of 1360 million children in sub-Saharan Africa from 2001 through 2005 resulting in a 60% reduction of deaths to 345000 from the previously calculated 873000. In Africa it is estimated that 506000 deaths had been reduced to 126000. In addition to measles vaccination the campaigns of the consortium have provided polio vaccine tetanus toxoid (to women of childbearing age) antihelminthics vitamin A oral rehydration solution soap and insecticide-treated bed nets. Their next expressed goal is a global 90% reduction in measles-associated mortality by 2010.Preliminary data suggest they may have already achieved an 85% reduction by the end of 2006. (excerpt)

To evaluate the prognostic value of surrogate markers (HIV RNA copy number, CD4 counts and CDC clinical and immunologic categories) in HIV-infected children through a 2-year period.Eighty-six HIV-infected children followed by the Duke Pediatric HIV Clinic in the fall of 1994 were evaluated for plasma HIV RNA concentration (viral load), CD4 lymphocyte percentage, age, antiretroviral treatment status and CDC clinical and immunologic categories. Follow-up evaluations were performed for approximately 2 years, and the time to progression to a new CDC category C diagnosis or death was noted.Of 86 children 22 had progression to new Category C diagnosis or death. Seven children died, 17 had a new Category C diagnosis and 2 had both. Among children who progressed, the median CD4 percentage at entry was 3% (absolute count, 75 cells/mm3), whereas children who had no disease progression entered with a median of 29% (868 cells/mm3). The overall median viral load at study entry was 4.58 log10 copies/ml (38,019 copies/ml, with a range of 1.7 to 6.78 logs). Children who had no disease progression had a median log copy number of 4.43, whereas 5.18 was the median for children whose disease progressed. Log copy number declined over time in children3 years of age, whereas it remained fairly consistent for children 3 years or older. Progression rates were determined by entry plasma HIV RNA concentration quartiles [quartile boundaries4.18, 4.58,5.08 log RNA copy/ml (15,136, 38,019 and120,226 copies/ml, respectively)]. Progression rates by quartile were 0 of 21, 4 of 22, 5 of 21 and 13 of 22. Kaplan-Meier survival curves defined by CD4% less than or greater than 15 and log RNA less than or greater than 5.0 (100,000) revealed that patients with CD4% less than 15 and plasma HIV RNA concentration5 log10 copies/ml did least well: 11 of 12 (92%) had a progression event at a median of 179 days. Patients with a high CD4 percentage and high viral load, or a low CD4 percentage and low viral load did similarly; 5 of 14 (36%) and 4 of 12 (33%) had progression events, respectively. Patients with high CD4 percentage and low viral load did best: only 2 of 48 (4%) had a progression event.The two most significant prognostic indicators of disease progression were the initial CD4 percentage and the plasma HIV RNA concentration, and a combination of CD4 percentage and virus load best predicted which children had progression events. Progression was less common in children who had100,000 HIV RNA copies/ml initially (6 of 60 vs. 16 of 26; P0.001; relative risk 0.16). Therefore it seems reasonable that in a child for whom complete suppression is not possible, a threshold of 100,000 (5 log10 copies/ml) can be used to mandate a change in therapy.

Initiated by a report in 1998 by Wakefield et al1 that the onset of a syndrome of ileal-lymphoid-nodular hyperplasia and nonspecific colitis accompanied by pervasive developmental disorder had appeared shortly after receipt of measles-mumps-rubella (MMR) vaccine by 8 children, the vaccine was soon indicted as the etiology of autism spectrum disorders (ASDs). Subsequent reports elaborated on this theory, and several laboratories claimed to have detected measles virus or its genome in intestinal biopsies as well as peripheral blood mononuclear cells from such autistic children.2–4 Other reports described elevated levels of measles antibodies in children with autism.5 In this issue of Pediatrics , D’Souza et al6 present their detailed, careful laboratory studies that refute these claims and explain the errors that led to them. Within a short time after the initial report by Wakefield et al, many parents in the United Kingdom and the United States opted to refuse the MMR vaccine for their infants and children. One explanation offered by the original reporters was that simultaneous MMR vaccination might lead to an aberrant immune response resulting in persistent infection and increased permeability of an inflamed gastrointestinal tract. Such conditions permitted the transport of opiate-like peptides to the central nervous system resulting in the autism syndromes.7 These claims occurred at a time of recognition that reports … Address correspondence to Samuel L. Katz, MD, Duke University Medical Center, Division of Pediatric Infectious Disease, Box 2925, Durham NC 27710. E-mail: katz0004{at}mc.duke.edu

Since 1989 the disparate recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics' (AAP) Committee on Infectious Diseases (COID), “The Redbook Committee,” regarding the age at which the second dose of measles vaccine (usually measles, mumps, rubella [MMR]) should be given has posed a dilemma for pediatricians. Although the goals of each group were identical, the pragmatic aspects considered by the respective committees differed. The ACIP, focusing primarily on the public health community, knew that immunizing the “captive audience” at school entry would be the most efficient way of assuring administration of a second dose. The COID, focusing primarily on the practicing clinician, judged that the second dose at 10 to 12 years would more rapidly provide protection for those youngsters who …

Captured in the pages of this supplement of the Journal of Infectious Diseases is a glimpse of the tremendous progress that has occurred since the global polio eradication initiative was launched by the World Health Assembly (WHA) in 1988. Drawing inspiration from the successful smallpox initiative, the WHA resolved to eradicate polio from the world by the year 2000 [1]. As was the case with smallpox virus, poliovirus causes acute, nonpersistent infections; humans are the only reservoir; virus survival in the environment is finite; and immunization with vaccine interrupts virus transmission?collectively, these factors make poliovirus a candidate for eradication. Poliovirus is on target to become only the second virus in the history of humankind to be eradicated from the face of the earth. The World Health Organization (WHO) is leading a global partnership of international organizations and governments to implement the proven strategies for polio eradication in all remaining polio-endemic countries [2]. From 1988 through 1995, reported cases of paralytic polio declined by 8007o, from 35,251 cases in 1988 to 7024 cases in 1995 [3, 4]; preliminary data for 1996 suggest a further decrease by ^O07o compared with 1995. One of the key strategies for polio eradication is the administration of supplemental doses of oral poliovirus vaccine (OPV) during nationwide mass campaigns known as National Immunization Days (NIDs) [2]. NIDs provide two supplemental doses of OPV to all young children (generally those ^ years of age), regardless of their previous immunization status. The two rounds of NIDs are each conducted over a short period, usually 1-3 days, during the low season for poliovirus transmission, with an interval of 4-6 weeks between rounds. These mass

The study by Bellini et al. [1] in this issue of the Journal of Infectious Diseases pro vides a reassuring affirmation that what previously had been only a clinical/epi demiologic observation is indeed factual: measles vaccine viruses do not cause sub acute sclerosing panencephalitis (SSPE). Bellini and colleagues have also revealed that the incidence of SSPE is much higher after natural measles than previously had been appreciated. Using sophisticated lab oratory technology that was not available when SSPE was previously reported in the United States, these investigators exam ined brain tissue specimens obtained dur ing the resurgence of measles in the United States during 1989-1991, confirmed the diagnosis of SSPE, and, by use of genotype analysis, established wild-type measles vi ruses as the responsible etiologic agents. The authors demonstrated, by use of data gathered during the measles outbreak of 1989-1991, as well as by use of data col lected during earlier outbreaks, that the true incidence of SSPE was ~7-ll cases of SSPE/100,000 cases of measles, rather than the previously cited estimate of 1 case of SSPE/100,000 cases of measles. When a live attenuated measles virus vaccine was first licensed in the United States in 1963 [2], the etiology of SSPE was unknown. It was not until 1967-1969 that measles viruses were demonstrated to

ON SEPTEMBER 17,1994, Heather Whitestone was chosen as Miss America, the first ever with a disability. Her deafness has been the subject of much media attention. On September 16, 1994, the Atlanta Constitution ran a story in its front section about Whitestone stating, "At age 18 months, [she] almost died from an adverse reaction to a routine DPT (diphtheria, pertussis, tetanus) vaccination. It wiped out all but a tiny sliver of her hearing." 1 On September 18, the New York Times ran an Associated Press story in its first section stating "Miss Whitestone... lost her hearing at 18 months because of a reaction to a diphtheria-tetanus shot." 2 On September 19 the New York Times ran another story ascribing her deafness to a vaccination. 3 Not until September 26 did the New York Times publish a story stating that Whitestone's deafness was not due to a vaccination but actually resulted

control programs. In barely four decades since the measles virus was first isolated in cell cultures, safe and effective live attenuated measles vaccines have been developed and are now in use worldwide [2]. Currently, nearly 80^ of the world's children are immunized against measles and :M.5 million deaths from measles are prevented each year. Yet, neither the vaccine nor the immunization programs are optimal?their limitations continue to allow ~ 1 million infants

In Chasing Polio in Pakistan: Why the World’s Largest Public Health Initiative May Fail, Svea Closser, a Middlebury College assistant professor of anthropology, has written a thoughtful and provocative assessment of the Polio Eradication Initiative (PEI) based on her own field work in 2006–2007. Closser, married to a Pakistani man and fluent in Urdu, had access to field workers and government officials, and provides greater insight than might be expected from a Western author. As an anthropologist, Closser strove to evaluate the progress and deficits of the program from a political and societal perspective rather than a technical or operational one. The result is a very convincing evaluation of the causes of failures to date, and Closser extrapolates that the lessons learned in fighting polio in Pakistan might apply to problems in other nations and to eradication efforts for diseases such as measles and malaria. Pakistan is one of the four countries (along with Nigeria, India, and Afghanistan) in which polio has remained endemic since the World Health Assembly voted in 1988 to eradicate the disease by the year 2000. Ten years after that target date, Nigeria and India show promise of possibly attaining eradication in the next several years, whereas Pakistan and Afghanistan lag. Although the two nations have some similar problems, Pakistan’s are unique in several respects. Immense floods in the summer of 2010 ravaged the Swat valley, resulting in the displacement and migration of several millions of people, the absence of running water and electricity, the destruction of housing, the loss of crops and food supply, and the closure of at least 500 health clinics and facilities. Although these tragic developments transpired three years after Closser’s experiences and the preparation of her manuscript, much of what she portrays and professes is relevant in assessing the likelihood of success or failure of global eradication endeavors. Closser believes that because polio has been eradicated in the Americas and in most of Europe, Pakistani government leaders view this global program as a goal of the affluent nations imposed on them by WHO and the United Nations. To them, the priority of the disease pales in comparison to so many other national problems of much higher magnitude. Although they pay lip service to the PEI, there is marked foot dragging and false compliance in Islamabad’s call on district and province officials to implement vaccination efforts. Health initiatives in general are at the bottom of the national government’s agenda, and the burden of polio is perceived as minor relative to that of diarrheal disease, respiratory infections, and meningitis. The national government’s influence is unpredictable in a nation in which central government has variable success in effecting local action. As Closser points out, “District employees resisted the directives of their superiors in a number of ways, including refusal to work, falsification, corruption, false compliance, and direct confrontation.” Nevertheless, Closser notes that the mothers of infants and children “accepted polio vaccination without giving the matter much thought.” More than 40 international consultants were in Pakistan during Closser’s field work, each costing WHO about $10,000 per month for secured housing and chauffeured land cruisers. Meanwhile, the local vaccinators were paid $2.00 per day for a five-day week, traveling on foot through their assigned districts; supervisors might have a bicycle or, rarely, a motorcycle for transportation. These are but a few of the observations and conclusions that Closser clearly details in her pages. She argues that societal and political considerations, not virologic or immunologic factors, are preventing eradication. Rather than a top-down approach (i.e., Geneva to Islamabad to district offices), she advises collaborative operations in which diverse non-governmental organizations can work on site with local agencies in an amicable advisory capacity on a district-by-district basis (the WHO is not authorized to operate below the national offices in Islamabad). She suggests that partnership should replace authoritarian directives. The detailed operational information Closser has gathered and described so vividly cannot be found in PEI reports or scientific reviews. Hers is a revelation of problems that erode the daily implementation of the eradication initiative in Pakistan. In her conclusion, Closser states that “awareness of power relationships and resistance as well as formal planning for institutional flexibility would, I believe, better position eradication programs to reach their goals. Taking these steps might shift the balance from the possible toward the probable.” Those responsible for overall direction of the PEI would do well to read and consider her presentation. This reviewer, who has lengthy experience at the CDC and WHO levels, is persuaded that her refreshing anthropological approach may provide solutions to the persistent challenges that have postponed for more than a decade the attainment of global eradication of polio.