Development Of Combination Vaccines Research Articles

The future of vaccines, immunisation concepts and practice

Vaccines have prevented more deaths, disability and suffering than any other medical discovery or intervention. Recent breakthroughs in immunology and genomics offer the prospect of the development of many new prophylactic and therapeutic vaccines not only against infectious diseases but also for use in conditions such as allergy, autoimmunity and carcinogenesis where malfunction of the immune system undoubtedly plays a role. These hopeful perspectives are however dimmed by several counterproductive societal trends that include the spreading—although unjustified—belief that vaccines are not safe and may even be unnecessary, escalating costs of vaccine research, development, production and control that are exacerbated by political pressure on selling prices and expensive lawsuits by ‘victims’ of vaccination who claim excessive compensation. Negative media coverage of vaccine issues is adversely affecting acceptance of vaccination. In spite of these negative trends, vaccines should have a bright future, because it is increasingly being realised that prevention is not only better than cure but it is often also more cost–effective. A better understanding of the dynamics of microbial transmission in populations is leading to more rational immunisation practices on a global scale that could lead to eradication of several pathogens. Attention is being given to making vaccines more user-friendly through the development of combined vaccines and the introduction of less invasive inoculation techniques.

Analysis of the transition from oral polio vaccine to inactivated polio vaccine for primary immunization in a hospital-based primary care practice.

Analysis of the transition from oral polio vaccine to inactivated polio vaccine for primary immunization in a hospital-based primary care practice.

Humoral and cellular immune responses in mice immunized with recombinant Mycobacterium bovis Bacillus Calmette-Guérin producing a pertussis toxin-tetanus toxin hybrid protein.

The development of combined vaccines constitutes one of the priorities in modern vaccine research. One of the most successful combined vaccines in use is the diphtheria-pertussis-tetanus vaccine. However, concerns about the safety of the pertussis arm have led to decreased acceptance of the vaccine but also to the development of new, safer, and effective acellular vaccines against pertussis. Unfortunately, the production cost of these new vaccines is significantly higher than that of previous vaccines. Here, we explore the potential of live recombinant Mycobacterium bovis BCG producing the hybrid protein S1-TTC, which contains the S1 subunit of pertussis toxin fused to fragment C of tetanus toxin, as an alternative to the acellular vaccines. S1-TTC was produced in two different expression systems. In the first system its production was under the control of the 85A antigen promoter and signal peptide, and in the second system it was under the control of the hsp60 promoter. Although expression of the hybrid antigen was obtained in both cases, only the second expression system yielded a recombinant BCG strain able to induce both a specific humoral immune response and a specific cellular immune response. The antibodies generated were directed against the TTC part and neutralized toxin activity in an in vivo challenge model, whereas interleukin-2 production was specific for both parts of the molecule. Since protection against tetanus is antibody mediated and protection against pertussis may be cell mediated, this constitutes a first promising step towards the development of a cost-effective, protective, and safe combined vaccine against pertussis, tetanus, and tuberculosis.

Development of combination vaccines

Breakthroughs in molecular biology, biochemistry, process development, immunology and related fields have provided the means for improving current vaccines and developing new ones. The increasing availability of these vaccines is providing the unprecedented opportunity to prevent serious infectious diseases in different age groups and to significantly reduce associated morbidity and mortality. However, since the great majority of licensed and experimental vaccines in advanced clinical studies are injected, each new vaccine creates the need for additional needlesticks which could become so numerous as to discourage full compliance with immunization schedules. Therefore, the development of combination vaccines is a major way to assure compliance with immunization needs. The leading types of licensed and experimental vaccines which have been or may be made into combination vaccines will be described. In addition, key challenges common to the development of all combination vaccines will be discussed; these include pharmaceutical, immunological, clinical, regulatory, manufacturing, public health and marketing issues. In order to assure timely development and availability of such combination products, these issues must be integrated successfully early in a development program.

Development and clinical application of new polyvalent combined paediatric vaccines

The availability of combined vaccines containing protective antigens against the majority of (ideally all) diseases for which universal immunization is recommended in infancy would simplify the implementation, increase the acceptance, reduce the global cost of immunization programmes and improve disease control, while offering the possibility of disease elimination or even pathogen eradication. The desirability of combined vaccines is further enhanced, and made more urgent, because of the increasing number of diseases that can be prevented by vaccination. The complicated logistics of administering different vaccines that each require several inoculations is a significant barrier to successful immunization of a population. Furthermore, interest in immunization is continuously gaining momentum since it is now generally recognised that vaccines are among the safest and most cost-effective medical interventions for infectious diseases that continue, in spite of the widespread use of efficacious antimicrobial drugs, to be an important cause of morbidity and mortality. This burden is likely to increase due to the development of antimicrobial resistance. Basic research on new vaccines or improvement of existing ones such as the use of new technologies may be carried out in academic or other non-industrial laboratories but development work, including the necessary extensive clinical testing, that lead to products that can be approved for routine use is usually co-ordinated and financed by commercial companies. The decision to develop any particular combined vaccine will therefore be influenced not only by its medical desirability and technical feasibility but also the potential financial returns that the required investments in time and resources may bring to the company. All major vaccine manufacturers are currently working, either alone or through strategic alliances, towards developing more polyvalent vaccines by adding antigens such as inactivated polio virus, conjugated Haemophilus influenzae type b polysaccharide and hepatitis B surface antigen to the diphtheria–tetanus–pertussis vaccine either in its `classical' (whole-cell) or more purified (acellular) formulations. Experience is showing that the development of combined vaccines involves much more than the simple mixing of existing antigens. Possible incompatibilities or mutual interferences between the antigens themselves, or between excipients, preservatives, adjuvants, residual contaminants, stabilisers and suspending fluids make it mandatory that each formulation be thoroughly tested for quality, stability, efficacy and safety. Furthermore the ability to produce and control it consistently must be established before it can be licensed for commercial use. The progress being made in this field is reviewed.

Acute respiratory infections (ARI) in children: prospects for prevention

Acute respiratory infections (ARI) are a major cause of morbidity in children worldwide, and are estimated to cause four million deaths per year, mainly in the developing world. In those countries, bacterial infection with high case fatality is common, apparently following a primary viral infection. The case management strategy has had success in controlling severe outcomes. However, its dependence on the use of antibiotics and the advantage of primary prevention support the need for vaccines. Vaccines against viruses such as respiratory syncytial and parainfluenza would prevent what is often the initial infection and vaccines against Haemophilus influenzae and S. pneumoniae the major bacterial causes of mortality. Maternal immunization may have special relevance in developing countries where protection early in life is required. The development of combination vaccines would also be especially useful, since contacts with the medical system are often difficult. The introduction and use of new vaccines in those regions will require demonstration of cost effectiveness and acceptance by policy makers.

Practical Considerations in Converting from Plasma-Derived to Recombinant Hepatitis B Vaccines

Plasma-derived and recombinant vaccines have been developed to prevent hepatitis B virus infections. Both types of vaccine perform very well with respect to safety, immunogenicity and protective efficacy. The protection afforded by both types of vaccine is satisfactory for at least 5 to 10 years after vaccination, and a further booster dose is not necessary during this period. However, the plasma-derived vaccine is costly to produce and there is an unjustified but prevalent fear that it may be contaminated by potential pathogens. The supply of human plasma for production of the plasma-derived vaccine cannot be assured once use of hepatitis B vaccines becomes universal. It is therefore inevitable that the recombinant vaccine will replace the plasma-derived vaccine. If necessary, both vaccines can be used in combination. Future directions for hepatitis B vaccine development include: determination of the need for incorporation of pre-S gene products to enhance immunogenicity; defining a practical strategy to combat the problem of escape mutants after vaccination; and development of combination vaccines containing other inactivated antigens to allow complete immunisation against several diseases with a minimal number of injections.

The Need for and Design of Combination Vaccines

Combination vaccines, by increasing the number of antigens that can be delivered at a single visit, will dramatically extend the range of diseases preventable by childhood immunization. As the antigenic possibilities and researchers’ technical capabilities increase, the rational design and development of combination vaccines become especially complex. A variety of epidemiological, medical, physicochemical, and commercial considerations are taken into account by manufacturers in determining which set(s) of antigens make “sense “ as combinations. A key challenge will be to predict and/or influence which antigens will be recommended for inclusion in the infant schedules in key markets in the coming years. Resource constraints dictate that companies must minimize the numbers of combinations to be developed, while at the same time offer combinations appropriate to different markets around the globe.

Can we reduce the dose of a vaccine?

This paper describes the planning, implementation, and analysis of a clinical trial to develop a pediatric vaccine against the tick-borne encephalitis virus. The trial was primarily a dose-finding study with the following objectives: the protein content of the vaccine should be lower than that of the vaccine for adults (which was already approved) in order to reduce reactogenicity, especially the rate of fever reactions, in children. At the same time, the protein content had to be high enough so that the immunogenicity of the pediatric vaccine would be at least equivalent to that of the vaccine for adults. We discuss in detail the definition of the equivalence criterion and the considerations concerning sample size calculation. The methods described in this paper are also useful for designing clinical trials for the development of combined vaccines.

Pediatric Immunization: Current Recommendations and Controversies

The prevention of life-threatening childhood infections through vaccination is a remarkable achievement in the history of medicine. Although 98% of all American children are fully immunized at age 5 to 6 years because state laws require it for school entry, in 1991 less than half of children younger than 2 years of age were up to date for their diphtheria, tetanus, and pertussis (DTP); polio; measles, mumps, and rubella (MMR), and Haemophilus influenzae type b (HIB) immunizations. These children are at greatest risk for life-threatening infection. The last decade has seen many changes in the recommendations for routine childhood immunization. The resurgence of measles led to the addition of a second measles immunization. The introduction of the HIB vaccine has had a significant impact on the incidence of dreaded childhood meningitis. The effort to reduce adverse events associated with the pertussis component of the DTP vaccine resulted in the development of a new pertussis vaccine. The oral polio vaccine (OPV) is still being used with much debate on the merits of the inactivated polio vaccine (IPV). The hepatitis B vaccine was recently incorporated into the childhood immunization schedule in an attempt to eliminate this costly and devastating disease. The childhood disease chickenpox may become a disease of the past with the recent introduction of the varicella vaccine. With the multiplicity of new vaccines on the horizon, childhood immunization schedules will become more complex. To ameliorate an increase in the number of injections and physician visits, major efforts are currently being devoted to the development of combination vaccines, and the latest routine childhood immunization schedule has made every attempt to provide flexibility. The Children's Vaccine Initiative (CVI) defines a goal of developing a single supervaccine that "could be given once at or near birth, provide immunity for life, require no boosters, permit storage without refrigeration, obviate the use of needles and syringes and protect against as many as 20 diseases at once." To achieve this goal, enormous investments in research and development will be necessary. In the meantime, pharmacists can do much to encourage good immunization practices in their daily interaction with patients, and in so doing further the goals of pharmaceutical care. Copyright © 1996 by W.B. Saunders Company

Challenges in the development of combination vaccines.

There has been increased interest in the last decade in the development of new vaccines, especially for pediatric use. Newer vaccines that have been licensed and recommended for widespread pediatric immunization include those for Haemophilus influenzae type b (Hib), hepatitis B (HB), and most recently in some countries varicella and Bordetella pertussis (acellular pertussis). Clinical trials are ongoing in infants for vaccines for Streptococcus pneumoniae (pneumococcal), hepatitis A (HA), and Neisseria meningitidis (meningococcal), among others. As a consequence, there is a tremendous opportunity to prevent the morbidity and mortality associated with these infectious diseases and to do so with a significantly favorable cost:benefit. However, each new vaccine would require additional injections which may become so numerous as to discourage widespread immunization. As a consequence, medical practitioners, patients, parents and others are very interested in the development of combination vaccines, whereby individual vaccines are mixed before delivery for administration in a single injection. Such mixing can take place at the point of manufacturing or filling or within a syringe or vial at the time of immunization.

Immunization and the prevention of childhood diseases.

Nursing has an important role in improving the incidence of childhood immunization. An understanding of the immunologic deficiencies of children, especially those younger than 5 years, demonstrates the need for this population-wide protection. Knowledge of the various products, their efficacy, schedule, side effects, and contraindications will assist the neonatal and pediatric nurse in coordinating immunizations and teaching parents about this important health priority for their children. Research is focusing on the development of combination vaccines and products for infectious diseases that currently have difficult or nonexistent treatment.

Development of Combined Vaccines: Manufacturers' Viewpoint

Abstract. Rapid and exciting research breakthroughs in the fields of immunology and molecular biology in recent years have greatly enhanced the potential for developing new vaccines or improving existing ones. The resulting rising number of diseases that can be prevented by vaccination, coupled with the growing trend of preferring cost-effective preventive medical interventions over expensive therapeutic modalities, has increased the complexity of administering to all those who need them, the many different vaccines that will soon be available. Hence attention in the field of vaccinology is now focusing on the development of combined vaccines that, in a few inoculations, can elicit protection against as many diseases as possible. Some of the recent achievements, future objectives and difficulties of vaccine manufacturers in the development of combined vaccines are surveyed.

Bivalent Vaccines Against Bacterial Enteropathogens: Construction of Live Attenuated Vaccine Strains With Two O-Serotype Specificities

Abstract. A considerable interest exists worldwide in the development of live attenuated oral vaccines against diarrhoeal diseases. In addition to vaccination against the corresponding pathogens, such vaccine strains can be used as carriers for the expression of protective antigens from other organisms. The antigenic repertoire of a given vaccine strain may thereby be extended, potentially leading to a bivalent vaccine. The lipopolysaccharide is known to be a major antigenic surface component of bacterial enteric pathogens. The feasibility of the development of combined vaccines based on live attenuated carriers expressing two O-serotype specificities is illustrated here by the development of candidate live oral vaccines against Shigella sonnei using Salmonella typhi and Vibrio cholerae as carriers. Various factors that may limit the potential of such hybrid strains as bivalent vaccines are discussed.