Estimated Public Health Impact of the Recombinant Zoster Vaccine.

OBJECTIVE: To investigate the potential public health impact of adult herpes zoster (HZ) vaccination with the adjuvanted recombinant zoster vaccine (RZV) in the United States in the first 15 years after launch. METHODS: We used a publicly available model accounting for national population characteristics and HZ epidemiological data, vaccine characteristics from clinical studies, and anticipated vaccine coverage with RZV after launch in 2018. Two scenarios were modeled: a scenario with RZV implemented with 65% coverage after 15 years and a scenario continuing with zoster vaccine live (ZVL) with coverage increasing 10% over the same period. We estimated the numbers vaccinated, and the clinical outcomes and health care use avoided yearly, from January 1, 2018, to December 31, 2032. We varied RZV coverage and investigated the associated impact on HZ cases, complications, and health care resource use. RESULTS: With RZV adoption, the numbers of individuals affected by HZ was predicted to progressively decline with an additional 4.6 million cumulative cases avoided if 65% vaccination with RZV was reached within 15 years. In the year 2032, it was predicted that an additional 1.3 million physicians' visits and 14.4 thousand hospitalizations could be avoided, compared with continuing with ZVL alone. These numbers could be reached 2 to 5 years earlier with 15% higher RZV vaccination rates. CONCLUSION: Substantial personal and health care burden can be alleviated when vaccination with RZV is adopted. The predicted numbers of HZ cases, complications, physicians' visits, and hospitalizations avoided, compared with continued ZVL vaccination, depends upon the RZV vaccination coverage achieved.

Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging.

The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research. In particular, it will be important to better understand how environmental factors, such as diet, physical activity, co-morbidities, and pharmacological treatments, delay or contribute to the decline of the capability of the aging immune system to appropriately respond to infectious diseases and vaccination. Recent findings suggest that successful approaches specifically targeted to the older population can be developed, such as the high-dose and adjuvanted vaccines against seasonal influenza, the adjuvanted subunit vaccine against herpes zoster, as well as experimental interventions with immune-potentiators or immunostimulants. Learning from these first successes may pave the way to developing novel and improved vaccines for the older adults and immunocompromised. With an integrated, holistic vaccination strategy, society will offer the opportunity for an improved quality of life to the segment of the population that is going to increase most significantly in numbers and proportion over future decades.

Immunogenicity and safety of a respiratory syncytial virus fusion protein (RSV F) nanoparticle vaccine in older adults.

BACKGROUND: A preventative strategy for Respiratory Syncytial Virus (RSV) infection constitutes an under-recognized unmet medical need among older adults. Four formulations of a novel recombinant RSV F nanoparticle vaccine (60 or 90 µg RSV F protein, with or without aluminum phosphate adjuvant) administered concurrently with a licensed inactivated trivalent influenza vaccine (TIV) in older adult subjects were evaluated for safety and immunogenicity in this randomized, observer-blinded study. RESULTS: A total of 220 healthy males and females ≥ 60 years of age, without symptomatic cardiopulmonary disease, were vaccinated concurrently with TIV and RSV F vaccine or placebo. All vaccine formulations produced an acceptable safety profile, with no vaccine-related serious adverse events or evidence of systemic toxicity. Vaccine-induced immune responses were rapid, rising as early as 7 days post-vaccination; and were comparable in all formulations in terms of magnitude, with maximal levels attained within 28 (unadjuvanted) or 56 (adjuvanted) days post-vaccination. Peak anti-F protein IgG antibody levels rose 3.6- to 5.6-fold, with an adjuvant effect observed at the 60 µg dose, and a dose-effect observed between the unadjuvanted 60 and 90 µg regimens. The anti-F response persisted through 12 months post-vaccination. Palivizumab-competitive antibodies were below quantifiable levels (<33 µg/mL) at day 0. The rise of antibodies with specificity for Site II peptide, and the palivizumab-competitive binding activity, denoting antibodies binding at, or in proximity to, antigenic Site II on the F protein, closely paralleled the anti-F response. However, a larger proportion of antibodies in adjuvanted vaccine recipients bound to the Site II peptide at high avidity. Day 0 neutralizing antibodies were high in all subjects and rose 1.3- to 1.7-fold in response to vaccination. Importantly, the RSV F vaccine co-administered with TIV did not impact the serum hemagglutination inhibition antibody responses to a standard-dose TIV, and TIV did not impact the immune response to the RSV F vaccine. CONCLUSIONS: RSV F protein nanoparticle vaccine induced increases in measures of functional immunity to RSV in older adults and demonstrated an acceptable safety profile. Adjuvanted formulations provided additional immunogenicity benefit as compared to increasing antigen dose alone. This trial was registered with ClinicalTrials.gov number NCT01709019.

Concurrent Oral Antipsychotic Drug Use Among Schizophrenia Patients Initiated on Long-Acting Injectable Antipsychotics Post-Hospital Discharge.

Pharmacological treatment is central to effective management of schizophrenia. Prescribing clinicians have an increasing array of options from which to choose, and oral antipsychotic polypharmacy is common in routine clinical practice. Practice guidelines recommend long-acting injectable (LAI) formulations, typically viewed as monotherapeutic alternatives, for patients with established nonadherence. Yet there are limited data on the prevalence and nature of concurrent oral antipsychotic prescriptions in patients receiving LAIs. Our observational, claims-based study examined the frequency and duration of concurrent oral prescriptions in 340 Medicaid patients receiving LAI therapy. Specifically, we examined patients with a recent history of nonadherence and hospitalization for schizophrenia and included both first-generation antipsychotic depot medications (fluphenazine decanoate, haloperidol decanoate) and more recently available second-generation injectables (LAI risperidone, paliperidone palmitate). Of all patients initiated on LAIs, 75.9% had a concurrent oral antipsychotic prescription in the 6 months post-hospital discharge. Patients receiving concurrent prescriptions were frequently prescribed an oral formulation of their LAI agent, but many first-generation LAI users received a concurrent second-generation oral medication. The lowest rate of concurrent prescribing (58.8%) was found with paliperidone palmitate, whereas the highest rate was with LAI risperidone (88.9%). Overlap in oral and LAI prescriptions typically occurred for a substantial period of time (ie, >30 days) and for a notable percentage of the days covered by LAIs (often 50% or more). Our findings highlight the need to further examine such prescribing patterns, to probe the reasons for them, and to clarify the optimal roles of different antipsychotic treatments in clinical practice.

Effective influenza vaccines for children: a critical unmet medical need and a public health priority.

Seasonal influenza causes clinical illness and hospitalization in all age groups; however, conventional inactivated vaccines have only limited efficacy in young children. MF59(®), an oil-in-water emulsion adjuvant, has been used since the 1990s to enhance the immunogenicity of influenza vaccines in the elderly, a population with waning immune function due to immunosenescence. Clinical trials now provide information to support a favorable immunogenicity and safety profile of MF59-adjuvanted influenza vaccine in young children. Published data indicate that Fluad(®), a trivalent seasonal influenza vaccine with MF59, was immunogenic and well tolerated in young children, with a benefit/risk ratio that supports routine clinical use. A recent clinical trial also shows that Fluad provides high efficacy against PCR-confirmed influenza. Based on the results of clinical studies in children, the use of MF59-adjuvanted vaccine offers the potential to enhance efficacy and make vaccination a viable prevention and control strategy in this population.

Clinically based surveillance of invasive meningococcal disease in young children admitted to selected US hospitals between January 2000 and June 2009: a retrospective cohort study.

Invasive meningococcal disease (IMD) is under-reported in countries that do not employ polymerase-chain reaction for surveillance because culture-negative cases are omitted. To evaluate a clinically based, case-finding method, we developed case definitions for "probable," "compatible with," and "possible, but unlikely" IMD, respectively, based on supportive documentation (e.g., discharge diagnosis of meningococcal infection, culture-negative bacterial meningitis, petechiae/purpura, Gram-negative diplococci on Gram stain) and weight of clinical evidence, which we then applied to electronic health records for all children aged ≤5 y who were admitted to approximately 100 US hospitals between January 2000 and June 2009. Among 47,863 qualifying admissions, 16 children had culture-positive IMD, 5 had "probable" IMD, and 5 had illness "compatible with" IMD. Five additional children had disease considered "possible but unlikely" IMD. Our case-finding methods suggest that culture-based ascertainment may underestimate the number of IMD cases by 31-63%, supporting findings in other nations that culture-based reporting provides incomplete information on disease incidence and therefore underestimates the potential benefits of routine vaccination of young children against meningococcal disease.

Critical appraisal of a quadrivalent CRM(197) conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo) in the context of treatment and prevention of invasive disease.

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo(®)) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need.

Ensuring the optimal safety of licensed vaccines: a perspective of the vaccine research, development, and manufacturing companies.

Vaccine safety is increasingly a focus for the general public, health care providers, and vaccine manufacturers, because the efficacy of licensed vaccines is accepted as a given. Commitment to ensuring safety of all vaccines, including childhood vaccines, is addressed by the federal government, academia, and industry. Safety activities conducted by the vaccine research, development, and manufacturing companies occur at all stages of product development, from selection and formulation of candidate vaccines through postlicensure studies and surveillance of adverse-event reports. The contributions of multiple interacting functional groups are required to execute these tasks through the life cycle of a product. We describe here the safeguards used by vaccine manufacturers, including specific examples drawn from recent experience, and highlight some of the current challenges. Vaccine-risk communication becomes a critical area for partnership of vaccine companies with government, professional associations, and nonprofit advocacy groups to provide information on both benefits and risks of vaccines. The crucial role of the vaccine companies in ensuring the optimal vaccine-safety profile, often overlooked, will continue to grow with this dynamic arena.

Optimizing protection against meningococcal disease.

Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia in the United States. Vaccines directed against meningococcal disease must elicit high and persistent titers of bactericidal antibodies against prevalent meningococcal serogroups and be highly efficacious in preventing meningococcal infection. Currently, 2 quadrivalent (A, C, W-135, Y) vaccines-a polysaccharide meningococcal vaccine and a conjugate meningococcal vaccine-are licensed in the United States. Neither is approved for use in infants or toddlers younger than 2 years of age. Results of studies with an investigational quadrivalent (ACWY) meningococcal CRM(197) glycoconjugate vaccine in infants demonstrate that this vaccine has potential to protect this age group. The availability of an effective vaccine for routine universal infant immunization is particularly important because the incidence of invasive meningococcal disease is greatest in infants for all serogroups and because achievable vaccination rates are much greater for infants and young children than they are for adolescents.

Effectiveness of school-based influenza vaccination.

BACKGROUND: Vaccination of children in school is one strategy to reduce the spread of influenza in households and communities. METHODS: We identified 11 demographically similar clusters of elementary schools in four states, consisting of one school we assigned to participate in a vaccination program (intervention school) and one or two schools that did not participate (control schools). During a predicted week of peak influenza activity in each state, all households with children in intervention and control schools were surveyed regarding demographic characteristics, influenza vaccination, and outcomes of influenza-like illness during the previous 7 days. RESULTS: In all, 47% of students in intervention schools received live attenuated influenza vaccine. As compared with control-school households, intervention-school households had significantly fewer influenza-like symptoms and outcomes during the recall week. Paradoxically, intervention-school households (both children and adults) had higher rates of hospitalization per 100 persons than did control-school households. However, there was no difference in the overall hospitalization rates for children or adults in households with vaccinated children, as compared with those with unvaccinated children, regardless of study-group assignment. Rates of school absenteeism for any cause (based on school records) were not significantly different between intervention and control schools. CONCLUSIONS: Most outcomes related to influenza-like illness were significantly lower in intervention-school households than in control-school households. (ClinicalTrials.gov number, NCT00192218.)

Benefits of and barriers to large medical group practice in the United States.

BACKGROUND: For decades, reformers argued that medical groups can efficiently provide high-quality care and a collegial professional environment. The growth of managed care and the movement to improve quality provide additional reasons for physicians to practice in groups, especially large groups. However, information is lacking on recent trends in group size and the benefits of and barriers to group practice. OBJECTIVES: To identify benefits of and barriers to large medical group practice, and to describe recent trends in group size. DESIGN, SETTING, AND PARTICIPANTS: Information on benefits and barriers was obtained from 195 interviews conducted during round 3 (2000-2001) of the Community Tracking Study with leaders of the largest groups, hospitals, and health insurance plans in 12 randomly selected metropolitan areas. Information on recent trends in group size was obtained from more than 6000 physicians in private practice in 48 randomly selected metropolitan areas via Community Tracking Study telephone surveys in 1997-1998, 1998-1999, and 2000-2001. MAIN OUTCOME MEASURES: Benefits of and barriers to large group practice, as perceived by interviewees, and changes in percentages of physicians in groups of varying sizes. RESULTS: Gaining negotiating leverage with health insurance plans was the most frequently cited benefit; it was cited 8 times more often than improving quality. Lack of physician cooperation, investment, and leadership were the most frequently cited barriers. Survey data indicate that 47% of private physicians work in practices of 1 or 2 physicians and 82% in practices of 9 or fewer, and that the percentage of physicians in groups of 20 or more did not increase between 1996 and 2001. CONCLUSIONS: Current payment methods reward gaining size to obtain negotiating leverage more than they reward quality. However, barriers to creating large medical groups are substantial, and most private physicians continue to practice in small groups, although the size of these groups is slowly increasing.

Referral gridlock: primary care physicians and mental health services.

BACKGROUND: Patients' barriers to mental health services are well documented and include social stigma, lack of adequate insurance coverage, and underdiagnosis by primary care physicians. Little is known, however, about challenges primary care physicians face arranging mental health referrals and hospitalizations. OBJECTIVE: To examine how practice setting and environment influence primary care physicians' ability to refer patients for medically necessary mental health services. DESIGN: Cross-sectional analysis using nationally representative survey data from the 1998 to 1999 Community Tracking Study physician survey. The overall survey response rate was 61%. PARTICIPANTS: A 1998 to 1999 telephone survey of 6586 primary care physicians. MEASUREMENTS: Primary care physicians' report of whether they could obtain medically necessary referrals to high-quality mental health specialists or psychiatric admissions. RESULTS: Overall, 54% of primary care physicians reported problems obtaining psychiatric hospital admissions, and 54% reported problems arranging outpatient mental health referrals. Primary care physicians practicing in staff and group model HMOs were much less apt to report difficulties than physicians in solo and small-group practices (P <.001). Reports of inadequate time with patients (P <.001) and smaller numbers of psychiatrists in a market area (P <.01) also were associated with problems obtaining mental health referrals. Pediatricians were more apt to report problems than general internists (P <.001). CONCLUSIONS: Primary care physicians face greater hurdles obtaining mental health services than other medical services. Primary care is an important entry point for mental health services, yet inadequate referral systems between medical and mental health services may be hampering access.

Hospitals' negotiating leverage with health plans: how and why has it changed?

OBJECTIVE: To describe how hospitals' negotiating leverage with managed care plans changed from 1996 to 2001 and to identify factors that explain any changes. DATA SOURCES: Primary semistructured interviews, and secondary qualitative (e.g., newspaper articles) and quantitative (i.e., InterStudy, American Hospital Association) data. STUDY DESIGN: The Community Tracking Study site visits to a nationally representative sample of 12 communities with more than 200,000 people. These 12 markets have been studied since 1996 using a variety of primary and secondary data sources. DATA COLLECTION METHODS: Semistructured interviews were conducted with a purposive sample of individuals from hospitals, health plans, and knowledgeable market observers. Secondary quantitative data on the 12 markets was also obtained. PRINCIPAL FINDINGS: Our findings suggest that many hospitals' negotiating leverage significantly increased after years of decline. Today, many hospitals are viewed as having the greatest leverage in local markets. Changes in three areas--the policy and purchasing context, managed care plan market, and hospital market--appear to explain why hospitals' leverage increased, particularly over the last two years (2000-2001). CONCLUSIONS: Hospitals' increased negotiating leverage contributed to higher payment rates, which in turn are likely to increase managed care plan premiums. This trend raises challenging issues for policymakers, purchasers, plans, and consumers.

Financial incentives and physicians' perceptions of conflict of interest and ability to arrange medically necessary services.

Many believe that physician payment mechanisms that include incentives to restrain utilization create conflicts of interest for physicians and result in the withholding of needed services. Pooled data from two rounds of the Community Tracking Study physician survey, a nationally representative telephone survey of physicians, are the basis of this analysis. We examine the association between explicit financial incentives linked to physician profiling and perceived conflict of interest, and the reported ability to obtain specific, medically necessary secondary services (referrals, hospitalizations and diagnostic imaging). Logistic regression models were employed to control for potentially confounding influences. After controlling for other factors, physicians subject to profiling linked with financial incentives were much less likely than physicians not affected by profiling to strongly agree that they can make clinical decisions in the best interests of their patients without the possibility of reducing their income. They were also less likely to report that they could always obtain selected medically necessary secondary services for their patients. Physicians subject to explicit financial incentives based on profiling are more likely than other physicians to perceive a conflict of interest. Physicians with financial incentives tied to profiling also experience greater difficulty obtaining medically necessary secondary services for their patients.

Physicians more likely to face quality incentives than incentives that may restrain care.

Concerns that physician financial incentives may lead to withholding needed care have caught the attention of legislators, regulators and even the U.S. Supreme Court. While the spotlight has been on how health plans reimburse physician practices, this Issue Brief provides unique nationally representative data on physician practices' use of incentives, which have a more direct effect on physician behavior. According to 1999 data from the Center for Studying Health System Change (HSC), physicians are more likely to be subject to incentives that may encourage use of services, such as patient satisfaction (24 percent) and quality (19 percent), than to financial incentives that may restrain care, such as profiling (14 percent). The complexity of physician financial incentives and their relatively low prevalence raise questions about effective regulation and public reporting of their use.