Global landscape analysis of no-fault compensation programmes for vaccine injuries: A review and survey of implementing countries.

To update the landscape analysis of vaccine injuries no-fault compensation programmes, we conducted a scoping review and a survey of World Health Organization Member States. We describe the characteristics of existing no-fault compensation systems during 2018 based on six common programme elements. No-fault compensation systems for vaccine injuries have been developed in a few high-income countries for more than 50 years. Twenty-five jurisdictions were identified with no-fault compensation programmes, of which two were recently implemented in a low- and a lower-middle-income country. The no-fault compensation programmes in most jurisdictions are implemented at the central or federal government level and are government funded. Eligibility criteria for vaccine injury compensation vary considerably across the evaluated programmes. Notably, most programmes cover injuries arising from vaccines that are registered in the country and are recommended by authorities for routine use in children, pregnant women, adults (e.g. influenza vaccines) and for special indications. A claim process is initiated once the injured party or their legal representative files for compensation with a special administrative body in most programmes. All no-fault compensation programmes reviewed require standard of proof showing a causal association between vaccination and injury. Once a final decision has been reached, claimants are compensated with either: lump-sums; amounts calculated based on medical care costs and expenses, loss of earnings or earning capacity; or monetary compensation calculated based on pain and suffering, emotional distress, permanent impairment or loss of function; or combination of those. In most jurisdictions, vaccine injury claimants have the right to seek damages either through civil litigation or from a compensation scheme but not both simultaneously. Data from this report provide an empirical basis on which global guidance for implementing such schemes could be developed.

Trends in vaccine investment in middle income countries.

Although a proven and effective preventive health measure, childhood immunization programs remain vulnerable to budgetary pressures. Sustainable financing of immunization programs is an important issue that presents a challenge for middle-income countries (MIC) in particular, in part due to technological advances meaning more vaccines are available. This study aimed to analyse trends in immunization program investment across 15 MIC selected based on availability of data, income level classification, and regional representativeness. We assessed investment trends in relation to vaccine coverage, vaccine access, and broader health indicators. Immunization and expenditure data were obtained from the World Health Organisation (WHO) database and the WHO UNICEF Joint Reporting Form and WHO Vaccine Product, Price and Procurement from 2006-2016. We calculated a weighted average index of vaccine commitment (WAIVC) based on vaccine coverage, vaccine scope, and weighted by vaccine innovation measured by approximating vaccine expenditure. Correlation analyses were conducted between immunization expenditure per-capita and each WAIVC, infant mortality and life expectancy. Correlation analyses at a global and individual country level indicate an improvement in immunization access, vaccination commitment measured by WAIVC, and scope of available vaccines in countries with sustained increases in vaccination funding. Increases in national immunization expenditure were correlated with reduced infant mortality and increased life expectancy. Vaccine expenditure comprises a small proportion (less than 2%) of total healthcare spending and has not uniformly increased in accordance with the scope of available vaccines. The present analysis supports the premise that countries with consistent increases in vaccine expenditure have increased vaccine coverage and commitment measured by WAIVC and improved broader health outcomes, indicating the value of sustained investment in vaccination for improved population health. The benefits of vaccine expenditure in this holistic fashion are critical to inform policy decisions on national budget allocation for vaccine funding.

Cost-effectiveness of grass pollen subcutaneous immunotherapy (SCIT) compared to sublingual immunotherapy (SLIT) and symptomatic treatment in Austria, Spain, and Switzerland.

BACKGROUND: While specific immunotherapy (SIT) has been proven to be cost-effective for the treatment of allergic rhinitis compared to symptomatic treatment, there is a lack of European studies in which sublingual (SLIT) and subcutaneous (SCIT) immunotherapy were compared. The present analysis is focused on the cost-effectiveness of SCIT compared to SLIT and symptomatic treatment of grass pollen allergy in Austria, Spain, and Switzerland. It will address specific properties of the underlying healthcare systems. METHODS: The investigation is based on a previously published health economic model calculation. This was designed as a Markov model with pre-defined health stages and a duration of 9 years covering specific preparations for SCIT (Allergovit) and SLIT (Oralair). The effectiveness was assessed as symptom-score based quality-adjusted life years (QALYs). Additionally, total cost has been determined as well as the cost-effectiveness of SCIT. The robustness of model results was proved in further sensitivity analyses. RESULTS: With regard to the effectiveness of both SCIT and SLIT, preparations were dominant compared to pharmacological symptomatic therapy. Both strategies were associated with additional cost, but, combined with the results on effectiveness, both have to be regarded as cost-effective. A direct comparison of the SCIT (Allergovit) and SLIT (Oralair) showed lower total costs of SCIT vs SLIT for Austria, Spain, and Switzerland (€1,368 vs €2,012, €2,229 vs €2,547, and €1,901 vs €2,220) and superior effectiveness (SCIT =8.02 QALYs; SLIT =7.98 QALYs; and symptomatic therapy =7.90 QALYs). CONCLUSION: In patients with allergic rhinitis, SIT offers cost-effective treatment options compared to symptomatic treatment. When comparing SCIT (Allergovit) and SLIT (Oralair), SCIT was dominant in terms of QALYs as well as costs, in particular due to a slightly higher patient compliance and lower drug costs.

An updated methodology to review developing-country vaccine manufacturer viability.

In 1997, Milstien, Batson, and Meaney published "A Systematic Method for Evaluating the Potential Viability of Local Vaccine Producers." The paper identified characteristics of successful vaccine manufacturers and developed a viability framework to evaluate their performance. This paper revisits the original study after two decades to determine the ability of the framework to predict manufacturer success. By reconstructing much of the original dataset and conducting in-depth interviews, the authors developed informed views on the continued viability of manufacturers in low- and middle-income country markets. Considering the marked changes in the market and technology landscape since 1997, the authors find the viability framework to be predictive and a useful lens through which to evaluate manufacturer success or failure. Of particular interest is how incumbent and potentially new developing-country vaccine manufacturers enter and sustain production in competitive international markets and how they integrate (or fail to integrate) new technology into the production process. Ultimately, most manufacturers will need to meet global quality standards to be viable. As governments and donors consider investments in vaccine producers, the updated viability factors will be a useful tool in evaluating the prospects of manufacturers over the mid to long term. The paper emphasizes that while up-front investments are important, other critical factors-including investments in a national regulatory authority, manufacturer independence, and ability to adapt and adopt new technology-are necessary to ensure viability.

Moving beyond traditional valuation of vaccination: Needs and opportunities.

Economic evaluations of vaccination traditionally focus on a relatively narrow set of vaccine benefits, such as averted medical care costs among those who are immunized. In recent years, researchers have identified additional vaccination benefits that should be incorporated into economic evaluations in order to reflect vaccination's full value. Early efforts to estimate the magnitude of these broader benefits suggest that vaccination has been substantially undervalued, which has important implications for public and private vaccine policy and human health and welfare. More and better data will be required to advance this emerging line of research on the value of vaccination. The article discusses promising data sources and methods and research questions needing to be addressed.

Are current cost-effectiveness thresholds for low- and middle-income countries useful? Examples from the world of vaccines.

The World Health Organization's CHOosing Interventions that are Cost Effective (WHO-CHOICE) thresholds for averting a disability-adjusted life-year of one to three times per capita income have been widely cited and used as a measure of cost effectiveness in evaluations of vaccination for low- and middle-income countries (LMICs). These thresholds were based upon criteria set out by the WHO Commission on Macroeconomics and Health, which reflected the potential economic returns of interventions. The CHOICE project sought to evaluate a variety of health interventions at a subregional level and classify them into broad categories to help assist decision makers, but the utility of the thresholds for within-country decision making for individual interventions (given budgetary constraints) has not been adequately explored. To examine whether the 'WHO-CHOICE thresholds' reflect funding decisions, we examined the results of two recent reviews of cost-effectiveness analyses of human papillomavirus and rotavirus vaccination in LMICs, and we assessed whether the results of these studies were reflected in funding decisions for these vaccination programmes. We found that in many cases, programmes that were deemed cost effective were not subsequently implemented in the country. We consider the implications of this finding, the advantages and disadvantages of alternative methods to estimate thresholds, and how cost perspectives and the funders of healthcare may impact on these choices.

Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization.

Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23°C, inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport.

Development pathway for biodefense vaccines.

At the present time it is estimated that the process of development of a vaccine from discovery to licensure takes approximately 18-20 years and costs in excess of US$500 million. For "routine" vaccines, the case for developing a vaccine is straightforward in terms of economics and large scale public health utilization each year. For vaccines used for biodefense and emerging diseases, the considerations are somewhat different as the vaccine may not be needed every year to control outbreaks and may be stockpiled only as a countermeasure that hopefully may never be needed. Furthermore, efficacy trials are often difficult as the natural disease may be rare or not present. Consequently, animal models will play a critical role in demonstrating efficacy. Nonetheless, the vaccine pathway still requires the same fundamental components of basic science/discovery, preclinical development, clinical trials, registration/licensure, and a plan for implementation.

Advances in predicting and manipulating the immunogenicity of biotherapeutics and vaccines.

Therapeutic proteins are vital to the future of human health provision and the survival and profitability of the global pharmaceutical industry. Returns from protein therapeutics are experiencing unprecedented growth: both their number and their economic dividend have increased by an order of magnitude in the last 10 years. The potential immunogenicity of protein therapeutics raises many clinical and safety concerns. Many poorly understood factors relating to both product and host affect immune responses. Available laboratory measurement of immunogenicity is of little utility for predicting the clinical properties of biotherapeutics. Coupled with assay variability and standardization issues, this precludes adequate prediction of the biological or clinical responses of therapeutic proteins, arguing for the utilization of informatic strategies in the analysis and prediction of protein immunogenicity. Currently, many unresolved issues must be addressed and thus circumvented before effective prediction can become routine.

Advance market commitments for vaccines against neglected diseases: estimating costs and effectiveness.

The G8 is considering committing to purchase vaccines against diseases concentrated in low-income countries (if and when desirable vaccines are developed) as a way to spur research and development on vaccines for these diseases. Under such an 'advance market commitment,' one or more sponsors would commit to a minimum price to be paid per person immunized for an eligible product, up to a certain number of individuals immunized. For additional purchases, the price would eventually drop to close to marginal cost. If no suitable product were developed, no payments would be made. We estimate the offer size which would make revenues similar to the revenues realized from investments in typical existing commercial pharmaceutical products, as well as the degree to which various model contracts and assumptions would affect the cost-effectiveness of such a commitment. We make adjustments for lower marketing costs under an advance market commitment and the risk that a developer may have to share the market with subsequent developers. We also show how this second risk could be reduced, and money saved, by introducing a superiority clause to a commitment. Under conservative assumptions, we document that a commitment comparable in value to sales earned by the average of a sample of recently launched commercial products (adjusted for lower marketing costs) would be a highly cost-effective way to address HIV/AIDS, malaria, and tuberculosis. Sensitivity analyses suggest most characteristics of a hypothetical vaccine would have little effect on the cost-effectiveness, but that the duration of protection conferred by a vaccine strongly affects potential cost-effectiveness. Readers can conduct their own sensitivity analyses employing a web-based spreadsheet tool.

Home delivery of heat-stable vaccines in Indonesia: outreach immunization with a prefilled, single-use injection device.

Extending immunization coverage to underserved populations will require innovative immunization strategies. This study evaluated one such strategy: the use of a prefilled, single-use injection device for outreach immunization by village midwives. The device, UniJect, is designed to prevent refilling or reuse. Stored at ambient temperatures for up to 1 month in midwives' homes, vaccine-filled UniJect devices were immediately available for outreach. Between July 1995 and April 1996, 110 midwives on the Indonesia islands of Lombok and Bali visited the homes of newborn infants to deliver hepatitis B vaccine to the infants and tetanus toxoid to their mothers. Observations and interviews showed that the midwives used the device properly and safely to administer approximately 10,000 sterile injections in home settings. There were no problems with excessive heat exposure during the storage or delivery of vaccine. Injection recipients and midwives expressed a strong preference for the UniJect device over a standard syringe. Use of the prefilled device outside the cold chain simplified the logistics and facilitated the speed and efficiency of home visits, while the single-dose format minimized vaccine wastage.

PIP: Recent studies have found that up to 30% of injections given for immunization are not sterile. Disposable syringes are reused and reusable syringes are often improperly sterilized. Findings are presented from an evaluation of the use of a prefilled, single-use injection device for outreach immunization by village midwives. Such devices can reduce the transmission of bloodborne pathogens and diseases, and reduce vaccine wastage associated with multi-dose vials. The device evaluated, UniJect, is designed to prevent refilling or reuse. Stored at ambient temperatures for up to 1 month in midwives' homes, vaccine-filled UniJect devices were immediately available for use. Between July 1995 and April 1996, 110 midwives on the Indonesian islands of Lombok and Bali visited the homes of newborn infants to deliver hepatitis B vaccine to infants and tetanus toxoid to their mothers. Observations and interviews found that the midwives safely and properly used the device to administer approximately 10,000 sterile injections in home settings. No problems were experienced with excessive heat exposure during the storage or delivery of vaccine. Injection recipients and midwives strongly preferred the UniJect device over a standard syringe. Furthermore, use of the prefilled device outside of the cold chain simplified the logistics and facilitated the speed and efficiency of home visits, while the single-dose format minimized vaccine wastage.

The Jeremiah Metzger Lecture. Vaccine prophylaxis today: its science, application and politics.

In summary, I have addressed 5 key issues concerning vaccines today. First is the essentially empiric nature of vaccinology. Vaccinology is not a rational science. Each idea must be tested by experiment. This need for trial and error experimentation is a substantial barrier to new vaccines. The proven track record of existing vaccines to eradicate disease, to reduce occurrence of disease, reduce human suffering and contain health care spending--when coupled with the potential for new discoveries against significant disease targets--is unparalleled by other therapeutic areas. The complexity of vaccine delivery today in clinical practice with 15-17 injections in the first two years of life emphasizes the need for development of combination pediatric vaccines, for example, putting DTaP, HBV, HIB, and IPV together. This has proved to be far more difficult than previously believed due to unpredicted immune interference and incompatibilities on mixing of different components, demonstrating again the inadequacy of our understanding of how vaccines work and the empiric nature of the science. Similar complexity will face adult vaccines in the future, as new adult vaccines are developed. Next, vaccines remain undervalued by people, by government, and by society. Government-controlled prices in many areas of the world prohibit a return on investment that supports innovative R&D. New vaccines may be unavailable in certain markets because of pricing restraints. Prices of new vaccines in the developed world will rise as will prices in the developing world for products currently available only in the developed world. Reluctance to use vaccines is an especially disturbing symptom of the undervaluation issue. In the U.S., school entry requirements have kept childhood immunization rates high by five years of age. But this is a new phenomenon, driven in part by the measles outbreaks. The risk is that history will repeat itself. In the absence of disease and lack of public knowledge of these diseases, complacency sets in, immunization rates fall, with the expected result on occurrence of disease. For adults, we may hope that managed care with its interest in cost saving and disease prevention may actually help in achieving the goals of the Year 2000. Finally, I have talked about the anti-vaccine attitudes and forces that impede control of disease by vaccines. It is important that new initiatives be undertaken that will be successful in providing a balanced view of vaccine safety, efficacy and benefits to the public, to the provider and to the payers.

Barriers to measles and pertussis immunization: the knowledge and attitudes of Pennsylvania primary care physicians.

OBJECTIVES: To understand the causes of low childhood immunization rates, physicians were interviewed about their knowledge, attitudes, and self-reported immunization practices. METHODS: Trained interviewers conducted a standardized telephone survey of physicians. A random sample of Pennsylvania family physicians, pediatricians, and general practitioners younger than 65 years of age who were in office-based practices was selected from the combined listings of the American Medical Association and American Osteopathic Association. Physicians seeing > or = 5 patients per week under age 6 years, seeing a total of > or = 15 patients per week, and having > or = 50% primary care patients were eligible. Of 383 eligible physicians, 70% (268) responded. The questionnaire was designed using the Health Belief Model, immunization barriers, and input from practitioners in primary care, pediatric infectious disease, maternal/ child health, and preventive medicine. RESULTS: Respondents were more likely to refer to public vaccine clinics those children without insurance (P < .001) or with Medicaid (P < .001) than children with insurance. Almost all (> 90%) respondents thought that vaccine efficacy was high and that the likelihood of serious side effects was low. However, only 37% gave estimates that corresponded with the literature regarding the likelihood of an infant with pertussis to need hospitalization. Many respondents used invalid vaccine contraindications; for instance, 37% would not administer MMR to a boy whose mother was pregnant. Many respondents (21%) would not administer four vaccines simultaneously. CONCLUSIONS: If the Healthy People 2000 goal to eliminate indigenous cases of measles is to be achieved, free vaccine supplies and increased provider education are needed.

Vaccine stability in the context of vaccine delivery in a developing country: India.

Infant immunisation coverages of 80-85% have become sustainable throughout the developing world. The vaccine market is enormous in developing countries; in 1992, the total consumption of vaccine doses amounted to 2207 millions. There were only 127 million births, and the actual doses given to infants would have been fewer than 1000 million. This indicates huge wastage, which could be saved if vaccines were more stable at high temperatures and did not become contaminated. The vaccine delivery problems are compounded by the rural residence of the majority of the population and by the reliance on village health workers who are not the optimum health care providers. Under these circumstances, post-marketing epidemiological surveillance of vaccine-preventable diseases is absolutely necessary to monitor vaccine performance which is a function of the efficacy of the products and their potency when delivered.

Experience with veterinary vaccines in warm climates.

After a short description of the African laboratories manufacturing veterinary vaccines, the authors explain the main constraints for the use, in the field, of veterinary vaccines in warm climates. The need to respect the cold chain from the supplier of vaccines to the recipient animal is emphasised. In the Ivory Coast, during national vaccination campaigns, it has been proved that the quality of the rinderpest and contagious bovine pleuropneumonia vaccines is satisfactory when there is no disruption in the cold transport services. The data of this survey are exposed. In the framework of a project entitled "Thermostable rinderpest Vaccine, Transfer of Technology", a thermostable vaccine has been developed. It is manufactured in different African laboratories and integrated in some Pan African Rinderpest Campaign (PARC) vaccination programmes. On the other hand, the prospects offered by new thermotolerant attenuated vaccines against Newcastle disease are exposed. Finally, the authors present an outlook on the development of thermoresistant veterinary vaccines, such as those produced by genetic engineering, in particular with pox virus vectors.