Methods of ensuring vaccine safety

With a decreasing disease burden from vaccine-preventable diseases in developed countries, ensuring the safety of vaccines is critically important for maintaining public confidence in vaccination programs and continuing low levels of disease. This will require investment in resources to identify true adverse effects, understand their pathophysiology, and design and manufacture safer vaccines.     

Public fear of vaccination: separating fact from fiction

During the last two centuries, the world has seen a substantial increase in the number and availability of vaccines for the prevention of infectious disease. Smallpox vaccine remains the most celebrated vaccine-related achievement in human history, but worldwide reductions in many other diseases including measles, mumps, rubella, polio, diphtheria, and whooping cough (Bordetella pertussis) also illustrate the power of vaccination in controlling outbreaks of contagious diseases. Ironically, as advances in vaccination successfully limit disease outbreaks, the impact that these infectious agents once had on society becomes marginalized. Public confidence in vaccination may erode because of real or perceived risks associated with immunization, and this in turn may lead to lower vaccination coverage and loss of herd immunity. Here, we will discuss some of the elements associated with public perceptions and fear of vaccination and place these into the context of how deadly several vaccine-preventable childhood diseases can be if vaccination coverage is insufficient.     

Vaccination against malaria with live parasites

Despite nearly 80 years of vaccine research and control efforts, malaria remains one of the most prevalent of all infectious diseases. The fact that people living in regions in which malaria is endemic eventually develop immunity to the parasite and the disease suggest that it might be possible to develop vaccines against malaria. Although few vaccination trials were conducted with whole parasites, the only protocol that leads to the induction of sterile immunity in humans relies on immunization with attenuated parasites. This observation has spurred the search for subunit vaccines that aim to reproduce this protection. As yet, none of the current candidate subunit vaccines have achieved complete protection reproducibly. This failure, coupled with the recent advent of the genetically modified Plasmodium parasites, has led to a renewed interest in the use of live parasites for vaccination. This article reviews past studies, summarizes recent developments in this field and discusses the challenges to be overcome before mass immunization with live parasites could be envisaged.     

Valuing the broader benefits of dengue vaccination,with a preliminary application to Brazil

The incidence of dengue has been on the rise since at least the 1960s, bringing greater urgency to the need for a vaccine to prevent the disease. Recent advances suggest that the scientific world is moving closer to an effective dengue vaccine. However, there are concerns that the price of a future vaccine could limit its uptake. High prices, in addition to other challenges, have already weighed negatively in government decisions to include other new vaccines in national immunization programs, e.g., the pneumococcal, rotavirus, and human papillomavirus vaccines. Recent research on the value of vaccination, however, suggests that vaccination confers benefits that are often neglected by traditional economic evaluations. In the case of dengue, commonly overlooked benefits are likely to include reduced spending on outbreak control, averted losses in tourism flows, and avoided productivity losses due to long-term dengue sequelae. Accounting for these and other broader benefits of dengue vaccination could reveal significantly greater economic value and strengthen the case for inclusion of dengue vaccination in national immunization programs. In this article we discuss a framework for the broader value of vaccination and review its application in the context of dengue vaccination for Brazil.     

Lessons learned and applied: what the 20th century vaccine experience can teach us about vaccines in the 21st century

Most vaccines available in the United States have been incorporated into vaccination schedules for infants and young children, age groups particularly at risk of contracting infectious diseases. High universal vaccination coverage is responsible for substantially reducing or nearly eliminating many of the diseases that once killed thousands of children each year in the US. Despite the success of infant vaccinations, periods of low vaccination coverage and the limited immunogenicity and duration of protection of certain vaccines have resulted in sporadic outbreaks, allowing some diseases to spread in communities. These challenges suggest that expanded vaccination coverage to younger infants and adolescents, and more immunogenic vaccines, may be needed in some instances. This review focuses on the importance of infant immunization and explores the successes and challenges of current early childhood vaccination programs and how these lessons may be applied to other invasive diseases, such as meningococcal disease.     

Challenges for development of meningococcal vaccines in infants and children

Neisseria meningitidis causes significant disease in the form of severe sepsis syndrome or meningococcal meningitis. Owing to the susceptibility of the immune system in early life, the risk of disease after infection is significantly higher in infants. Thus far, vaccines targeted against meningococcal serogroups have struggled to provide lasting protection in young children. Even conjugate vaccines that are now routinely used in the immunization of infants require multiple dosing and the duration of protection has been shown to wane over time and require repeated booster doses. After briefly summarizing the current epidemiology according to age and serogroup, this article will consider the reasons for poor immunogenicity of vaccines in infants and will discuss the relative efficacy of the different vaccine types in this age group. It will then go on to consider strategies for optimizing the protection of infants against meningococcal disease.     

A review on the association between inflammatory myopathies and vaccination

Several viruses and vaccines are among the environmental factors implicated as triggers of autoimmune inflammatory myopathies. Case histories report on the onset of dermatomyositis/polymyositis after immunization with various vaccines of patients with probable genetic predisposition. However, retrospective and epidemiological studies failed to ascertain an association between DM/PM and vaccines: no significant increase in the incidence of DM/PM was reported after large vaccination campaigns. The risk for vaccine-induced adverse events may be enhanced by adjuvants. Macrophagic myofasciitis is a novel inflammatory myopathy ascribed to an ongoing local immune reaction to a vaccine adjuvant. Isolated prospective studies showed that the administration of unadjuvanted, non-live vaccine to patients with DM/PM caused no short-term harmful effects to DM/PM immune processes. However, more research is warranted to clarify the incidence of vaccine-preventable infections, harmful effects of vaccination, and the influence of any immunomodulating agents on vaccination efficacy. Vaccination is an important disease prevention tool in modern medicine. This review does not address risk–benefit or cost–benefit analyses, and does not advocate the use of specific vaccines or vaccination programs. Despite a great deal of scientific uncertainty, the concept of a possible causal link between immunization and inflammatory myopathies should not be totally rejected.     

Monitoring the impact of vaccines postlicensure: new challenges, new opportunities

Although vaccines are studied intensively before licensure, insight into important aspects of vaccine performance and the effectiveness of immunization programs and policies can only be detected after vaccines enter widespread use. Now that 17 diseases are targeted for prevention through routine immunizations in the USA, reassessment of the nation's vaccine-preventable disease-monitoring efforts is appropriate. Postlicensure disease monitoring has permitted recognition of indirect protection, vaccine effectiveness of various schedules, duration of protection, health disparities, importation patterns and microbial adaptation. The investments in vaccine research, development and regulatory procedures prelicensure, as well as resources devoted to purchase, distribution and delivery of vaccines after introduction, necessitate strategic efforts to monitor the impact of large-scale use of vaccines on disease over time.     

DNA immunization--a new chance in vaccine research?

A novel class of vaccines, based on the immunization with "naked" DNA, may hold the promise of protecting against human disease without the disadvantages associated with vaccines presently used, and may help to prevent infections which are not curable today. Direct intramuscular or intradermal inoculation of plasmid DNA encoding sequences of viral proteins results in the synthesis of these proteins, causing humoral and/or cellular immune responses in the recipient. Several advantages are associated with DNA immunization, e.g., cheap to produce, heat stability, amenable to genetic manipulation, mimic viral infection, and no risk of reversion to pathogenicity. Nevertheless, some concerns remain regarding their safety, e.g., the possible integration of plasmid DNA into host chromosomes. In summary, the results concerning the efficiency of DNA vaccination demonstrate clearly that these new vaccines may have a promising future in human immunization.     

Immunoprophylaxis of hepatitis B virus infection

Hepatitis-B infection is a global health problem. The spectrum of the disease is highly variable ranging from mild disease to chronic liver diseases including hepatocellular carcinoma. There are approximately 350 million chronic Hepatitis-B surface antigen (HBsAg) carriers in the world. Till date there is no effective therapy against this disease. Hence, prevention of the disease through vaccination is the only means to control the disease. Passive immunization is recommended for certain accidental exposures. Hepatitis-B immunoglobulin (HBIG) contains high titers of anti-HBs prepared from pooled plasma. HBIG has been shown to be highly effective in preventing post exposure transmission. HBIG induces immunity for a short period only hence, it is recommended to have a course of active immunization following passive immunization. Active immunization is achieved using vaccination. Two generations of vaccines, 1st generation plasma derived and 2nd generation recombinant DNA vaccines are available. Both these vaccines have been used extensively in all age groups all over the world. The studies have shown that HB vaccines are clinically well tolerated, safe and highly immunogenic. Normally 3 doses of HB vaccines are recommended in 0, 1, 2 and 12 or 0, 1, 6 months schedule. The dosages and schedules may vary in certain special groups, such as infants and neonates, chronic renal failure patients on hemodialysis. Advisory committee on immunization practices (ACIP) has given several guidelines regarding HB vaccination. Universal immunization of all infants and integration of HB Vaccine in the expanded program of immunization has been recommended by World Health Organization. Universal infant immunization is cost effective. Universal immunization of infants is the only strategy that will lead to the control and eradication of HBV infection in all regions of the world. Several countries have adopted this policy. But in India we have several problems in implementation of this policy. The high cost of the presently available vaccine is one of the major factors. The future consideration for hepatitis vaccines are focussed on multivalent combination vaccines with other childhood vaccines, and use of immunomodulators in conjunction with vaccine to increase the efficacy of vaccines in immunocompromised hosts.     

Vaccination of patients with auto-immune inflammatory rheumatic diseases requires careful benefit-risk assessment

Will vaccination raise the incidence of autoimmune diseases, what is the impact of increasingly crowded vaccination schedules, the vaccination in age groups and the risk of coincidental temporal association? All these issues are still under debate. However, for the time being, to avoid confusion in the medical community and the media, we have to adhere to guidelines established consensually by experts while ensuring a strict surveillance and reporting possible side effects. Recommendation for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD) based on the currently available evidence and expert opinion were recently formulated by an EULAR task force. Major recommendations for AIIRD include: i) vaccination should ideally be administered during stable disease; ii) influenza vaccination and pneumococcal vaccination should be strongly considered; iii) vaccination can be administered during the use of DMARDs and TNF-inhibitors, but before starting rituximab; iv) live attenuated vaccines should be avoided whenever possible in immunosuppressed patients; v) BCG vaccination is not recommended.     

Impact of conjugate pneumococcal vaccines on the changing epidemiology of pneumococcal infections

Streptococcus pneumoniae-related infections have a major global impact on healthcare, especially in the developing world, and are considered the number one vaccine-preventable cause of death in children. There are more than 90 pneumococcal serotypes and 46 serogroups. The first capsular polysaccharide pneumococcal vaccine was licensed in the USA in 1977 for individuals older than 2 years of age at high risk for pneumococcal disease. Two decades later, the first 7-valent pneumococcal polysaccharide-protein conjugate vaccine completed the required clinical trials and was introduced as part of the national immunization program of various countries. New-generation vaccines that include emerging serotypes, while maintaining protection against the 7-valent pneumococcal serotypes, have recently been approved. With the addition of these serotypes, the majority of potential pneumococcal serotypes causing invasive disease in most parts of the world could be covered.     

Oral vaccine delivery: can it protect against non-mucosal pathogens?

Vaccination is an efficient and cost-effective form of preventing infectious diseases. However, most currently available vaccines are delivered by injection, which makes mass immunization more costly and less safe, particularly in resource-poor developing countries. Oral vaccines have several attractive features compared with parenteral vaccines, but studies on their use have been limited almost exclusively to protection against mucosally transmitted pathogens. Their potential for controlling non-mucosally transmitted diseases has not yet been appreciated in general. In this article, we provide evidence that oral immunization is a feasible alternative for preventing infections transmitted through non-mucosal routes, including infections such as malaria, Japanese encephalitis and hepatitis B. Although there are still hurdles to overcome before such approaches can be deployed widely, recent progress in the oral vaccination field and the availability of a range of delivery systems offers hope for the development of a larger number of oral vaccines.     

Vaccinations for adult solid-organ transplant recipients: current recommendations and protocols

Recipients of solid-organ transplantation are at risk of severe infections due to their life-long immunosuppression. Despite emerging evidence that vaccinations are safe and effective among immunosuppressed patients, most vaccines are still underutilized in these patients. The efficacy, safety, and protocols of several vaccines in this patient population are poorly understood. Timing of vaccination appears to be critical because response to vaccinations is decreased in patients with end-stage organ disease and in the first 6 months after transplantation. For these reasons, the primary immunizations should be given before transplantation, as early as possible during the course of disease. Vaccination strategy should include vaccination of household contacts and health care workers at transplant centers unless contraindicated. No conclusive data are available on the use of immunoadjuvants and screening for protective titers. Most vaccines appear to be safe in solid-organ transplantation recipients, but live vaccines should be avoided until further studies are available. The risk of rejection appears minimal. Recommended vaccines include pneumovax, hepatitis A and B, influenza, and tetanus-diphtheria. We outline specific protocols and recommendations in this particular patient population. Specific contraindications exist for other vaccines, such as yellow fever, oral polio vaccine, bacillus Calmette-Guerin, and vaccinia. We conclude that solid-organ recipients will benefit from consistent immunization practices. Further studies are recommended to improve established protocols in this patient population.     

What's new in vaccines against herpes simplex infections?

Herpes simplex viruses (HSV) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy HSV infections remain a public health problem. Vaccines offer the possibility for controlling the spread and limiting HSV disease, two strategies for herpes vaccination: prophylactic immunization or therapeutic immunization. The article discusses the results of different studies, in particular, concerning recombinant vaccines, DISC vaccines and DNA vaccines.     

Pathology of vaccine-preventable infectious disease and the central nervous system

Infections of the central nervous system are important sources of morbidity and mortality worldwide. The risk for infections with specific bacterial, viral, fungal and parasitic agents varies greatly with the patient's age, immune status, prior vaccination history, seasonality and geographic exposures. While vaccines are available for many viral and bacterial pathogens, there has been a resurgence of vaccine-preventable diseases in recent years due to under-vaccination of eligible children and adults. This review will discuss key pathognomonic features of vaccine-preventable infectious diseases of the central nervous system that may be encountered in general surgical and autopsy practice.     

Vaccines against fungal infections

The state-of-the-art reached in developing protective immunity against fungal infections through vaccination makes a survey of methodologies and results timely. This review describes experimental vaccinations against dermatophytes, pathogenic yeasts, and dimorphic fungi with special attention to the anti-Coccidioides immitis vaccine, which has reached clinical trials, and to the anti-Candida albicans and anti-Histoplasma capsulatum ribosomal vaccines. Also covered are vaccination experiments in compromised hosts aimed at eliciting acquired resistance to opportunistic fungal infections which constitute risk factors for these hosts. Immunization procedures include live, killed, and attenuated organisms, as well as different subcellular fractions such as cytoplasmic extracts, fungal culture filtrates, cell walls, or ribosomal fractions. A variety of experimental animal models and isolated human trials constitute the subjects in these studies. Acquired immunity has been evaluated through assessment of resistance to infection and determination of specific immune responses. It has been demonstrated that fungal vaccines do elicit both humoral and cell-mediated immunity in the immunized host. For some vaccines (e.g., H. capsulatum), a correlation between the induced immunity and protection was observed and the immunity could be adoptively transferred. In view of the potential of vaccines against fungal infections, a perspective on their applicability, significance, and value for human use is discussed.     

Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?

The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to full-blown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine. So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome). The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive).     

Vaccine-preventable diseases and their impact on Latin American children

A joint meeting of the Latin American Society of Pediatric Infectious Diseases, the Dominican Society of Pediatrics and the Dominican Society of Vaccinology was held in the Dominican Republic. This report highlights the most relevant issues that were presented and discussed about vaccine-preventable diseases, their epidemiology and impact in Latin American children, the need to move forward and expand national immunization programs and the economical and political obstacles to introduce 'new' vaccines. These include those against Streptococcus pneumoniae, rotavirus, hepatitis A, varicella, Neisseria meningitidis, Bordetella pertussis, influenza and human papillomavirus, among others.     

Will the current measles vaccines ever eradicate measles?

Measles virus is the most infectious transmissible agent causing human disease and has probably been responsible for the deaths of more children than any other single cause. In addition, infection with the natural virus causes many severe complications, including encephalitis, deafness and pneumonia. The introduction of live attenuated vaccines, either singly or as the measles-mumps-rubella combined vaccine, has dramatically reduced the occurrence of disease and in countries where vaccine uptake is high, indigenous disease has been virtually eliminated. Even though the current vaccines are very efficient, they do have their limitations. Children are most at risk during the first year of life and for most of this period, maternal antibodies prevent effective immunization. In addition, the current measles vaccines are relatively heat labile which causes difficulty in tropical areas. In recent years, vaccination rates in some industrial countries have been adversely affected by fears that measles vaccines are linked to inflammatory bowel diseases and autism. Although there is no conclusive evidence to support these fears, they still remain and probably contribute to poor vaccine uptake in some regions and sections of society. Although severe complications from vaccination are extremely rare, mild local reactions are more common. Consequently, in countries where measles is declining or has been eliminated, the fear of side effects of vaccination may encourage the development of vaccines that do not rely on virus replication to take effect.