The impact of vaccine procurement methods on public health in selected European countries.

Introduction: Across Europe, immunization programs have brought immense benefits to the prevention of infectious diseases. The vaccines used are procured through a variety of models such as tenders and Pricing & Reimbursement. However, to date, the impact of the procurement method on the performance and sustainability of vaccination programs and on public health has received little attention.Areas covered: Drawing on a review of the academic and policy literature, complemented by an interview program with stakeholders involved in the procurement of vaccines, the authors have documented the relationship between procurement method dynamics and the level of protection against vaccine-preventable diseases in Germany, Italy, Spain and Romania for, measles-containing vaccines, hexavalent and influenza vaccines.Expert opinion: Price-based tenders can contribute to vaccine supply issues, discourage the provision of value-added services supporting vaccination coverage and disincentives future R&D. Although it is observed that price-based tenders can intensify competition in the short term, there can be unintended consequences such as damage to long-term competition. As European countries are committed to strengthen their immunization programs, they should consider the implications of current vaccine procurement models on the vaccine ecosystem and on public health.

Current situation, causes, and countermeasures to NIP vaccine shortages in Guangzhou, China.

From 2017 to 2018, Guangzhou experienced a shortage in 3-6 types of National Immunization Program (NIP) vaccines. To evaluate the current situation and causes of the NIP vaccine shortage, we analysed the duration, intensity and causes of the shortage from data in the vaccine information system of the Guangzhou Center for Disease Control and Prevention; we also proposed countermeasures to resolve the shortage. In 2017, there were shortages of three types of NIP vaccines in Guangzhou. The most affected vaccines were inactivated poliovirus (IPV) vaccine and meningococcal group AC (MenAC) vaccine, accounting for 39.5% and 16.5% of the reported shortages, respectively. In 2018, the shortage extended to six vaccine types; the most affected were diphtheria, tetanus and pertussis (DTP) vaccine, MenAC vaccine, and Bacille Calmette Guerin (BCG) vaccine. The four main causes for the shortage were: 1) an insufficient production capacity; 2) a delay in batch issuance; 3) vaccine-related events; and 4) an extended bidding procurement cycle. Four solutions are proposed: 1) expand production output; 2) exempt creditworthy enterprises from batch inspections; 3) establish alternative enterprises and emergency use authorizations; and 4) establish public health funds and stockpile storage systems.

Manufacturing DTaP-based combination vaccines: industrial challenges around essential public health tools.

INTRODUCTION: The manufacture of DTP-backboned combination vaccines is complex, and vaccine quality is evaluated by both batch composition and conformance of manufacturing history. Since their first availability, both the manufacturing regulations for DTP combination vaccines and their demand have evolved significantly. This has resulted in a constant need to modify manufacturing and quality control processes. Areas covered: Regulations that govern the manufacture of complex vaccines can be inconsistent between countries and need to be aligned with the regulatory requirements that apply in all countries of distribution. Changes in product mix and quantities can lead to uncertainty in vaccine supply maintenance. These problems are discussed in the context of the importance of these products as essential public health tools. Expert commentary: Increasing demand for complex vaccines globally has led to problems in supply due to intrinsically complex manufacturing and regulatory procedures. Vaccine manufacturers are fully engaged in the resolution of these challenges, but currently changes in demand need ideally to be anticipated approximately 3 years in advance due to long production cycle times.

Estimated costs attributable to events of "out-of-temperature" in the stockpiling of hexavalent vaccines occurring in Italy.

BACKGROUND: Antigens contained in vaccines are inherently unstable biologically; such a characteristic is conferred by their three-dimensional structure. Preserving the ability of the vaccines to protect against disease is necessary to ensure the supervision and monitoring of all steps of the cold chain. DTPa-HBV-IPV/Hib vaccine (Infanrix hexaTM, GSK Vaccines, Belgium) is designed to prevent disease due to diphtheria, tetanus, pertussis (DTP), hepatitis B virus (HBV), poliomyelitis and Haemophilus influenzae type b (Hib); it was first licensed for use in Europe in 2000 and is currently licensed in at least 95 countries. Since October 2013, more than 102 million doses of GSK's DTPa-HBV-IPV/Hib vaccine have been distributed globally, with nearly 15 million doses distributed in Italy. DTPa-HBV-IPV/Hib components are stable up to a temperature of 25°C for 72 hours. Lacking of officially approved stability data may generate some concern in case of cold chain accidents. METHODS: An analysis based on collected data was carried out to estimate potential costs attributable to events of "out-of-temperature" in the stockpiling of hexavalent vaccines occurring in Italy in 2014. RESULTS: The analysis, based on real data, documented that the loss for the National Health Service (NHS) was in the range of 100,000 - 400,000 euros in one year. However, the amount of money that in principle could have been lost would have ranged between nearly half and one million euros/year. CONCLUSIONS: A substantial loss of money was avoided thanks to the availability of officially approved stability data for GSK's DTPa-HBV-IPV/Hib vaccine.

Determining the optimal vaccine vial size in developing countries: a Monte Carlo simulation approach.

Outreach immunization services, in which health workers immunize children in their own communities, are indispensable to improve vaccine coverage in rural areas of developing countries. One of the challenges faced by these services is how to reduce high levels of vaccine wastage. In particular, the open vial wastage (OVW) that result from the vaccine doses remaining in a vial after a time for safe use -since opening the vial- has elapsed. This wastage is highly dependent on the choice of vial size and the expected number of participants for which the outreach session is planned (i.e., session size). The use single-dose vials results in zero OVW, but it increases the vaccine purchase, transportation, and holding costs per dose as compared to those resulting from using larger vial sizes. The OVW also decreases when more people are immunized in a session. However, controlling the actual number of people that show to an outreach session in rural areas of developing countries highly depends on factors that are out of control of the immunization planners. This paper integrates a binary integer-programming model to a Monte Carlo simulation method to determine the choice of vial size and the optimal reordering point level to implement an (nQ, r, T) lot-sizing policy that provides the best tradeoff between procurement costs and wastage.

Societal impact of combination vaccines: experiences of physicians, nurses, and parents.

Crowded immunization schedules can result in missed or delayed dosing. Combination vaccines help immunize children on time, limit the required number of injections, and allow new vaccines to be added to the schedule. In the United States, a pentavalent vaccine combining diphtheria, tetanus toxoids, and acellular pertussis (DTaP), recombinant hepatitis B (HepB), and inactivated poliovirus vaccine (IPV) is available. Here, we describe the findings of informal surveys among providers, nurse managers, business managers, and parents on their attitudes toward and experiences with the DTaP-HepB-IPV vaccine. Combination vaccine use is expected to increase as more become available and awareness of their benefits grows.

Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP).

Two live, attenuated varicella zoster virus-containing vaccines are available in the United States for prevention of varicella: 1) a single-antigen varicella vaccine (VARIVAX, Merck & Co., Inc., Whitehouse Station, New Jersey), which was licensed in the United States in 1995 for use among healthy children aged > or = 12 months, adolescents, and adults; and 2) a combination measles, mumps, rubella, and varicella vaccine (ProQuad, Merck & Co., Inc., Whitehouse Station, New Jersey), which was licensed in the United States in 2005 for use among healthy children aged 12 months-12 years. Initial Advisory Committee on Immunization Practices (ACIP) recommendations for prevention of varicella issued in 1995 (CDC. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1996;45 [No. RR-11]) included routine vaccination of children aged 12-18 months, catch-up vaccination of susceptible children aged 19 months-12 years, and vaccination of susceptible persons who have close contact with persons at high risk for serious complications (e.g., health-care personnel and family contacts of immunocompromised persons). One dose of vaccine was recommended for children aged 12 months-12 years and 2 doses, 4-8 weeks apart, for persons aged > or = 13 years. In 1999, ACIP updated the recommendations (CDC. Prevention of varicella: updated recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1999;48 [No. RR-6]) to include establishing child care and school entry requirements, use of the vaccine following exposure and for outbreak control, use of the vaccine for certain children infected with human immunodeficiency virus, and vaccination of adolescents and adults at high risk for exposure or transmission. In June 2005 and June 2006, ACIP adopted new recommendations regarding the use of live, attenuated varicella vaccines for prevention of varicella. This report revises, updates, and replaces the 1996 and 1999 ACIP statements for prevention of varicella. The new recommendations include 1) implementation of a routine 2-dose varicella vaccination program for children, with the first dose administered at age 12-15 months and the second dose at age 4-6 years; 2) a second dose catch-up varicella vaccination for children, adolescents, and adults who previously had received 1 dose; 3) routine vaccination of all healthy persons aged > or = 13 years without evidence of immunity; 4) prenatal assessment and postpartum vaccination; 5) expanding the use of the varicella vaccine for HIV-infected children with age-specific CD4+ T lymphocyte percentages of 15%-24% and adolescents and adults with CD4+ T lymphocyte counts > or = 200 cells/microL; and 6) establishing middle school, high school, and college entry vaccination requirements. ACIP also approved criteria for evidence of immunity to varicella.

Steps to success: getting children vaccinated on time.

Many children are not being vaccinated on time, putting them at risk for serious illness. There are many contributors to the delays in vaccination that occur, but global practice improvements can be made to reduce the risk of missed vaccination opportunities. One of the most effective ways to ensure on-time immunization is to use combination vaccines, thereby reducing the number of injections, a primary cause of missed doses. Nurses often play a pivotal role in delivering vaccinations and, thus, can lead initiatives to improve on-time immunization in their practices.

Overcoming constraints to meeting increased demand for Babesia bigemina vaccine in Australia.

Demand for live trivalent tick fever vaccine containing Babesia bovis, Babesia bigemina and Anaplasma centrale produced by the Department of Primary Industries, Queensland, has increased from less than 10,000 doses in 1988 to 500,000 doses in 2001. This paper describes a series of trials aimed at overcoming certain constraints to obtain B. bigemina parasitised erythrocytes (PEs) on a large enough scale from infected splenectomised calves to meet the demand. Passage through a series of splenectomised calves failed to increase the yield per calf but we showed that the dose rate of infected cells could be reduced from the long-time standard of 1x10(7) to 2.5x10(6) without affecting immunogenicity and still leaving a safety margin of at least 50-fold for infectivity. This change quadrupled the potential yield of doses per calf and allowed the DPI to meet the increased demand for B bigemina in vaccine. Due to the high cost and limited availability of suitable, health tested donors, calves previously infected with B. bovis or A. centrale were used to provide B. bigemina organisms but the practice resulted in red cell agglutination in some batches of prepared vaccine. A trial is described where B. bigemina-infected red cells were washed by centrifugation to remove agglutinating antibodies. Washing had no effect on parasite viability and this method is now in routine use in the production of trivalent vaccine.

Using Monte Carlo simulation to determine combination vaccine price distributions for childhood diseases.

The Recommended Childhood Immunization Schedule provides guidelines that allow pediatricians to administer childhood vaccines in an efficient and effective manner. Research by vaccine manufacturers has resulted in the development of new vaccines that protect against a growing number of diseases. This has created a dilemma for how to insert such new vaccines into an already crowded immunization schedule, and prompted vaccine manufacturers to develop vaccine products that combine several individual vaccines into a single injection. Such combination vaccines permit new vaccines to be inserted into the immunization schedule without requiring children to be exposed to an unacceptable number of injections during a single clinic visit. Given this advantage, combination vaccines merit an economic premium. The purpose of this paper is to describe how Monte Carlo simulation can be used to assess and quantify this premium by studying four combination vaccines that may become available for distribution within the United States. Each combination vaccine is added to twelve licensed vaccine products for six childhood diseases (diphtheria, tetanus, pertussis, haemophilus influenzae type B, hepatitis B, and polio). Monte Carlo simulation with an integer programming model is used to determine the (maximal) inclusion price distribution of four combination vaccines, by randomizing the cost of an injection. The results of this study suggest that combination vaccines warrant price premiums based on the cost assigned to administering an injection, and that further developments and innovations in this area by vaccine manufacturers may provide significant economic and societal benefits.

Considerations for combination vaccine development and use in the developing world.

As more vaccines are developed and become available, combination vaccines will provide a way of delivering multiple antigens to avoid multiple injections and complications in the regular immunization schedules. The advantages of combination vaccines are that they decrease the discomfort of vaccine recipients and parents and also reduce the delivery cost of vaccines. We address some of the issues related to the use of combination vaccines in the developing world. Which vaccines are needed? Do developing countries have the appropriate infrastructure to deliver them? Can vaccines become affordable for countries with low incomes? And what is really needed to achieve the goal of providing developing countries with new vaccines of epidemiologic significance in a timely fashion?

Manufacturing issues related to combining different antigens: an industry perspective.

Despite the growing demand for combination vaccines, many challenges have been encountered in developing them. It is difficult to predict the physical compatibility and stability of antigens in combination, because these characteristics are highly dependent on vaccine excipients. Clinical evaluation of potential modifications of efficacy of antigens in combination may be alleviated by use of appropriate animal models. Manufacturing issues, such as batch-release testing, storage of intermediate products, and the shift to preservative-free products, are of particular concern because they have the potential to affect the supply chain. Managing changes in the manufacture of one antigen that is a component of several different combination vaccines is also difficult. However, most potential issues can be resolved through the simplification of regulatory processes and harmonization of requirements, such as the acceptance of comparability protocols and antigen master files. Continued collaboration between industry and authorities is necessary to develop effective means of handling all submissions pertaining to combination vaccines.

[Influenza season 1998/99; composition of vaccine for 1999/2000]. / Het influenzaseizoen 1998/'99; vaccinsamenstelling voor 1999/2000.

The first indication of influenza activity in the Netherlands in the 1998/'99 season was the isolation of an influenza B virus in week 47 of 1998. In subsequent weeks influenza activity slowly increased, reaching a peak in week 6 of 1999. After a gradual decline for three weeks a second peak was reached in week 8 of 1999. The first wave of influenza activity was primarily caused by influenza B viruses, whereas during the second wave predominantly influenza A viruses of the A/H3N2 subtype were isolated. The antigenic properties of the influenza A viruses resembled those of the viruses isolated in the previous season and the vaccine strain A/Sydney/5/97. The influenza B viruses did not completely match with B/Harbin/7/94 which is most commonly used for vaccine production. The vaccine, however, did provide good protection against the epidemic strains of influenza. This season influenza A/H1N1 viruses did not play a significant part and only a small number of viruses of this subtype were isolated at the end of the season. For the influenza season 1999/2000 it is recommended by the World Health Organization that the vaccines contain the following (or similar) virus strains: A/Sydney/5/97 (H3N2), A/Beijing/262/95 (H1N1) and B/Beijing/184/93.

Combination vaccines for childhood immunization.

An increasing number of new and improved vaccines to prevent childhood diseases are being introduced. Combination vaccines represent one solution to the problem of increased numbers of injections during single clinic visits. This statement provides general guidance on the use of combination vaccines and related issues and questions. To minimize the number of injections children receive, parenteral combination vaccines should be used, if licensed and indicated for the patient's age, instead of their equivalent component vaccines. Hepatitis A, hepatitis B, and Haemophilus influenzae type b vaccines, in either monovalent or combination formulations from the same or different manufacturers, are interchangeable for sequential doses in the vaccination series. However, using acellular pertussis vaccine product(s) from the same manufacturer is preferable for at least the first three doses, until studies demonstrate the interchangeability of these vaccines. Immunization providers should stock sufficient types of combination and monovalent vaccines needed to vaccinate children against all diseases for which vaccines are recommended, but they need not stock all available types or brandname products. When patients have already received the recommended vaccinations for some of the components in a combination vaccine, administering the extra antigen(s) in the combination is often permissible if doing so will reduce the number of injections required. To overcome recording errors and ambiguities in the names of vaccine combinations, improved systems are needed to enhance the convenience and accuracy of transferring vaccine-identifying information into medical records and immunization registries. Further scientific and programmatic research is needed on specific questions related to the use of combination vaccines.