Vaccines administered simultaneously: directions for new combination vaccines based on an historical review of the literature.

OBJECTIVES: The recognized benefits of administering vaccines simultaneously has encouraged vaccine producers to develop combination vaccines. If contemporary research and development can realize vaccines that achieve the current standards for safety, immunogenicity, and efficacy, other specific vaccine associations may also merit reconsideration as combination vaccines. METHODS: An historical review of the vaccine association literature reveals two important themes: first, the programs of mass vaccination, in particular, the eradication of smallpox, sessions where multiple vaccines (other than the smallpox vaccine) were given concurrently, and the Expanded Programme on Immunization (EPI); and, second, the domain of travel vaccines, including travellers to a disease-endemic country (such as migrants, tourists, military personnel, or expatriates) and WHO requirements for international travellers. RESULTS/CONCLUSIONS: Based on this historical review, combination vaccines worth reconsideration could fill epidemiologic niches in the EPI with, for instance, a measles--yellow fever, a measles--Japanese encephalitis or a pertussis-based paediatric combination rabies vaccine. Furthermore, other combinations could broaden protection against the pathogens responsible for meningitis, pneumonia, or enteric diseases. Nevertheless, complex issues such as necessity, feasibility, or affordability will ultimately determine if any one of these becomes a combination vaccine.     

Immunization update and hot topics in clinical immunology: how does this relate to my practice?

The prevention of infectious diseases by the use of vaccines represents one of medicine's greatest triumphs during the 20th century. This era has witnessed the global eradication of smallpox as a result of Jennerian cowpox vaccination, the elimination of paralytic poliomyelitis from the western hemisphere, and within 5-10 years the anticipated eradication of poliomyelitis worldwide as a result of the poliovirus vaccines. Next slated for worldwide eradication is measles, the great killer of infants and children, which each year extracts a global mortality of one million victims. Throughout the 20th century the percutaneous (i.e., subcutaneous or intramuscular) route has almost exclusively been the preferred way to administer vaccines. However, as a result of several important scientific discoveries made during the 20th century, including new tissue-culturing techniques, the development of recombinant DNA technology, and genetic sequencing, a whole new generation of tailor-made modern vaccines has become available, including DNA vaccines and transgenic plant vaccines. Moreover, it became apparent that alternative routes of administration of vaccines, such as by aerosol immunization might be more appropriate and more effective than immunization via the parenteral route. The overall success in vaccine development, however, has not been without cost. For every new vaccine that has been developed, an adverse effect has been seen. Thus, although modern vaccines are extremely safe and effective, they are neither completely safe nor completely effective. The goal of vaccine development, therefore, is to achieve the highest degree of protection and the lowest rate of adverse effects. This paper describes some of the recent advances in vaccine development and will focus on some hot topics relating to the recent development and use of respiratory aerosolized vaccines.     

Immunomodulatory vaccination in autoimmune disease.

The development of vaccines is arguably the most significant achievement in medicine to date. The practice of innoculation with the fluid from a sore to protect from a disease actually dates back to ancient China; however, with the introduction of Jenner's smallpox vaccine, and greater understanding of the immune system, vaccines have become specific and systematic. Traditional vaccines have used killed pathogens (hepatitis A and the Salk polio vaccines), immunogenic subunits of a given pathogen (hepatitis B subunit vaccine), or live attenuated pathogens (measles, mumps, rubella, Sabin polio vaccines) to generate protective immunity. Currently, a new generation of vaccines that use the genetic material of a pathogen to elicit protective immunity are being developed. Although the most widespread and successful use of vaccines today remains in the arena of infectious diseases, manipulations of immune responses to protect against cancers, neurologic diseases, and autoimmunity are being explored rigorously.     

State of immunization in the Americas

Countries in the Americas have led the world in conquering infectious diseases preventable through vaccination. In 1971, the Western hemisphere achieved smallpox eradication. In 1991, the Americas were free of indigenous transmission of wild poliovirus. In 1998, overall regional vaccination coverage was 86% for diphtheria-pertussis-tetanus, 89% for oral poliovirus vaccine 3, 98% for bacille Calmette-Guérin vaccine, and 85% for measles. These figures confirm that most of the children in the Americas are protected against these diseases. The breakthroughs obtained in immunization have stimulated countries to promote new initiatives aimed at the control and eradication of other vaccine-preventable diseases and to introduce new vaccines into routine schedules. In the 21st century, vaccines will remain the most cost-effective means of preventing diseases and avoiding expensive treatment costs.     

Therapeutic Vaccines and Antibodies for Treatment of Orthopoxvirus Infections

Despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. The current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but because of safety issues, it is no longer given as a routine vaccine to the general population. In the event of serious human orthopoxvirus infections, it is important to have treatments available for individual patients as well as their close contacts. The smallpox vaccine and vaccinia immune globulin (VIG) were used in the past as therapeutics for patients exposed to smallpox. VIG was also used in patients who were at high risk of developing complications from smallpox vaccination. Thus post-exposure vaccination and VIG treatments may again become important therapeutic modalities. This paper summarizes some of the historic use of the smallpox vaccine and immunoglobulins in the post-exposure setting in humans and reviews in detail the newer animal studies that address the use of therapeutic vaccines and immunoglobulins in orthopoxvirus infections as well as the development of new therapeutic monoclonal antibodies.     

Development of a highly efficacious vaccinia-based dual vaccine against smallpox and anthrax, two important bioterror entities

Bioterrorism poses a daunting challenge to global security and public health in the 21st century. Variola major virus, the etiological agent of smallpox, and Bacillus anthracis, the bacterial pathogen responsible for anthrax, remain at the apex of potential pathogens that could be used in a bioterror attack to inflict mass casualties. Although licensed vaccines are available for both smallpox and anthrax, because of inadequacies associated with each of these vaccines, serious concerns remain as to the deployability of these vaccines, especially in the aftermath of a bioterror attack involving these pathogens. We have developed a single vaccine (Wyeth/IL-15/PA) using the licensed Wyeth smallpox vaccine strain that is efficacious against both smallpox and anthrax due to the integration of immune-enhancing cytokine IL-15 and the protective antigen (PA) of B. anthracis into the Wyeth vaccinia virus. Integration of IL-15 renders Wyeth vaccinia avirulent in immunodeficient mice and enhances anti-vaccinia immune responses. Wyeth/IL-15/PA conferred sterile protection against a lethal challenge of B. anthracis Ames strain spores in rabbits. A single dose of Wyeth/IL-15/PA protected 33% of the vaccinated A/J mice against a lethal spore challenge 72 h later whereas a single dose of licensed anthrax vaccine protected only 10%. Our dual vaccine Wyeth/IL-15/PA remedies the inadequacies associated with the licensed vaccines, and the inherent ability of Wyeth vaccinia virus to be lyophilized without loss of potency makes it cold-chain independent, thus simplifying the logistics of storage, stockpiling, and field delivery in the event of a bioterror attack involving smallpox or anthrax.     

Smallpox

The WHO declared smallpox eradicated in 1980. However, concern over its potential use by terrorists or in biowarfare has led to striking growth in research related to this much-feared disease. Modern molecular techniques and new animal models are advancing our understanding of smallpox and its interaction with the host immune system. Rapid progress is likewise being made in smallpox laboratory diagnostics, smallpox vaccines, and antiviral medications. WHO and several nations are developing stockpiles of smallpox vaccine for use in the event the disease is reintroduced. National and international public-health agencies have also drawn up plans to help with early detection of and response to a smallpox outbreak. These plans hinge on physicians' ability to recognise the clinical features of smallpox and to distinguish it from other illnesses characterised by rashes.     

Smallpox vaccine and its stockpile in 2005

Smallpox vaccine was the most important tool in the successful eradication of smallpox. In 1980, this achievement made it possible for all nations to cease smallpox vaccination. However, the threat of smallpox bioterrorism has made it necessary to reconsider the need for vaccination. Over the past 3 years, many nations have set up action plans for use in the event of such an attack. The setting up of these plans was not simple. Several factors needed to be considered, including the judgement of risk, vaccine complications, conventional vaccines versus new vaccines, optimal stockpile of smallpox vaccine, and its use for different target populations in different emergency situations. Here, I review measures taken by the USA, Japan, and other nations, and discuss likely national and global efforts in 2005 and subsequently, in view of the fact that half of the world's population is now apparently unvaccinated and that this proportion will increase with time.     

Status report on HIV vaccine development

In May, the World Health Organization (WHO) declared AIDS to be the world's deadliest infectious disease, and estimated that 16,000 new infections occur every day around the world. Many experts say that a vaccine is essential to sustain a decrease in the number of new infections. Although there has been considerable funding devoted to HIV vaccine development, it has not reached the level of funding for other vaccines, such as polio and smallpox. HIV mutates readily, which complicates vaccine development. Preventive (prophylactic), therapeutic (or treatment), fusion-competent, and Tat toxoid vaccines are discussed. Current vaccine strategies discussed include DNA, live vector-based, subunit, peptide, attenuated, virus-like particle (VLP), and inactivated vaccines. The requirements for a successful vaccine are identified, and contact information is given for several clinical trials currently underway. Contact information and Internet addresses are also provided for several organizations that support vaccine development.     

Smallpox vaccine safety is dependent on T cells and not B cells

The licensed smallpox vaccine, ACAM2000, is a cell culture derivative of Dryvax. Both ACAM2000 and Dryvax are administered by skin scarification and can cause progressive vaccinia, with skin lesions that disseminate to distal sites. We have investigated the immunologic basis of the containment of vaccinia in the skin with the goal to identify safer vaccines for smallpox. Macaques were depleted systemically of T or B cells and vaccinated with either Dryvax or an attenuated vaccinia vaccine, LC16m8. B cell depletion did not affect the size of skin lesions induced by either vaccine. However, while depletion of both CD4(+) and CD8(+) T cells had no adverse effects on LC16m8-vaccinated animals, it caused progressive vaccinia in macaques immunized with Dryvax. As both Dryvax and LC16m8 vaccines protect healthy macaques from a lethal monkeypox intravenous challenge, our data identify LC16m8 as a safer and effective alternative to ACAM2000 and Dryvax vaccines for immunocompromised individuals.     

Alternative routes of immunization for prevention of infectious diseases: a new paradigm for the 21st century.

The prevention of infectious diseases by the use of vaccines represents one of medicine's greatest triumphs during the 20th century. This era has witnessed the global eradication of smallpox as a result of Jennerian cowpox vaccination, the elimination of paralytic poliomyelitis from the western hemisphere, and within 5-10 years the anticipated eradication of poliomyelitis worldwide as a result of the poliovirus vaccines. Next slated for worldwide eradication is measles, the great killer of infants and children, which each year extracts a global mortality of one million victims. Throughout the 20th century the percutaneous (i.e., subcutaneous or intramuscular) route has almost exclusively been the preferred way to administer vaccines. However, as a result of several important scientific discoveries made during the 20th century, including new tissue-culturing techniques, the development of recombinant DNA technology, and genetic sequencing, a whole new generation of tailor-made modern vaccines has become available, including DNA vaccines and transgenic plant vaccines. Moreover, it became apparent that alternative routes of administration of vaccines, such as by aerosol immunization and transcutaneous skin patches, might be more appropriate and more effective than immunization via the parenteral route. This paper describes some of the recent advances relating to alternative methods of immunization and will focus primarily on the development and use of respiratory aerosolized vaccines.     

Quest for life-long protection by vaccination.

Life-long protection from disease through immunization can be accomplished through individual or community protection. Individual protection is the goal for vaccination against diseases that have inanimate or animal reservoirs or that pose risks for certain populations. Community protection is the goal for vaccination against diseases that are transmitted only from human to human. Community protection afforded by childhood vaccines has been highly successful against measles, rubella, mumps, and polio. However, outbreaks of measles, rubella, and mumps continue to occur, primarily because of inadequate immunization of children under age 2. Simplification of vaccination regimens, provision of incentives to care providers and parents, and increased access to care should improve vaccination rates in the United States. Better protection requires better use of available vaccines. Eradication of disease through vaccination is the ultimate goal of community protection. Elimination of the infectious agent is the most effective means of achieving life-long protection. The World Health Organization's (WHO) smallpox eradication campaign eliminated a serious disease as well as the need for a vaccine with frequent and severe adverse reactions. The discontinuation of smallpox vaccination in the United States has produced a savings of over $3 billion. Polio has been targeted by WHO for eradication by the year 2000. The eradication of polio and the elimination of the need for polio vaccination in the United States should result in a savings of $110 million per year in vaccine costs alone. Strong United States support is crucial for WHO to reach its goal. Any of the vaccine-preventable childhood virus diseases could be eradicated with sufficient national and international will. Measles and hepatitis B should be high priorities. The ultimate goal of vaccination is life-long protection of all individuals. Any disease of sufficient public health importance to warrant routine vaccination is of sufficient importance to warrant eradication wherever judged to be possible.     

Primary induction of human CD8+ cytotoxic T lymphocytes and interferon-gamma-producing T cells after smallpox vaccination

This study measured the ability of a standard smallpox vaccine, given by scarification (by bifurcated needle), to induce primary human vaccinia virus-specific cytotoxic and interferon (IFN)-gamma-producing T lymphocyte responses. Because protection against smallpox may be mediated in part by T cell memory responses induced by vaccination, an analysis of the induction of primary human cytotoxic T lymphocytes (CTL) and IFN-gamma-producing T cell responses was performed. Although smallpox is no longer an epidemic threat under natural conditions, vaccination is still recommended for persons working with vaccinia viruses in the laboratory and for those who may be at risk from the potential use of smallpox virus as a bioterrorism agent. The results demonstrate that smallpox vaccine given by bifurcated needle induces strong vaccinia virus-specific CD8(+) CTL and IFN-gamma-producing T cell responses and provide baseline information useful for planning the immunologic assessment of future smallpox vaccines.     

Vaccine herd effect

Vaccination ideally protects susceptible populations at high risk for complications of the infection. However, vaccines for these subgroups do not always provide sufficient effectiveness. The herd effect or herd immunity is an attractive way to extend vaccine benefits beyond the directly targeted population. It refers to the indirect protection of unvaccinated persons, whereby an increase in the prevalence of immunity by the vaccine prevents circulation of infectious agents in susceptible populations. The herd effect has had a major impact in the eradication of smallpox, has reduced transmission of pertussis, and protects against influenza and pneumococcal disease. A high uptake of vaccines is generally needed for success. In this paper we aim to provide an update review on the herd effect, focusing on the clinical benefit, by reviewing data for specific vaccines.     

Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses

The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus.     

Recent developments in tuberculosis vaccines

PURPOSE OF REVIEW: The aim is to review findings related to the use of Bacille Calmette-Guerin (BCG) vaccine, focusing on its limitations and benefits in controlling tuberculosis (TB). Some new TB vaccines, which have entered or are expected to enter clinical trials, are highlighted. RECENT FINDINGS: BCG is currently the only available vaccine against TB, and is widely administered within the World Health Organization Expanded Programme for Immunization. Several trials have shown that the protective efficacy of BCG varies between different populations. Recently, a 60-year follow-up study of American Indians reported the long-term efficacy of BCG to be 52%. The reasons for the low efficacy of the BCG vaccine may be generic differences in the BCG strains, differences in immunological properties of study populations or exposure to environmental factors such as mycobacteria. The low efficacy of the BCG vaccine has encouraged the search for a new vaccine. Among new vaccine candidates are live attenuated Mycobacterium tuberculosis vaccines, recombinant BCG, DNA vaccines, subunit vaccines and fusion proteins with novel adjuvants and delivery systems. SUMMARY: Today, most of the world's population is vaccinated with BCG. It is generally accepted that BCG protects against childhood TB but this immunity wanes with age, resulting in no or insufficient protection against TB. Using modern techniques, several research groups have developed more than 200 new vaccine candidates. Some of these vaccines are now in clinical trials. The clinical evaluation of these new vaccines should be designed to cover a heterogeneous population with great variation in immune responses.     

Smallpox and the Native American

With the arrival of Europeans in the Western Hemisphere, Native American populations were exposed to new infectious diseases, diseases for which they lacked immunity. These communicable diseases, including smallpox and measles, devastated entire native populations. In this article, we focus on the effect of smallpox on the Native Americans from the 15th through the 19th centuries. Among the "new" infectious diseases brought by the Europeans, smallpox was one of the most feared because of the high mortality rates in infected Native Americans. This fear may have been well-founded, because the Native Americans were victims of what was probably one of the earliest episodes of biological warfare. Fortunately, they were also major beneficiaries of early vaccination programs. Thus, the arrival of smallpox and the decline of the Native American populations are inexorably linked, as the history summarized here illustrates.     

Vaccinia viruses with a serpin gene deletion and expressing IFN-gamma induce potent immune responses without detectable replication in vivo

In a continuing effort to develop safe and efficacious vaccine and immunotherapeutic vectors, we constructed recombinant vaccinia virus (rVV) vaccines lacking either the B13R (SPI-2) or the B22R (SPI-1) immune-modulating gene and coexpressing IFN-gamma. B13R and B22R are nonessential VV immune-modulating genes that have antiapoptotic and antiinflammatory properties with sequence homology to serine protease inhibitors (serpins). IFN-gamma is a cytokine with potent immunoregulatory, antineoplastic, and antiviral properties. We observed that these rVVs with a deletion in a serpin gene and expressing IFN-gamma replicated to high titers in tissue culture yet were avirulent in both immunocompromised and immunocompetent mice with no detectable viral replication in these animals. A single immunization elicited potent humoral, T helper, and cytotoxic T cell immune responses in mice despite the absence of any detectable virus replication in vivo. IFN-gamma coexpression and the inactivation of one or more VV immune-modulating genes provide an optimized method for increasing the safety while maintaining the efficacy of rVV vaccines. This strategy provides a method for developing highly safe and efficacious vaccines for smallpox and other diseases and immunotherapeutic vectors.     

Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza

Large-scale immunization has profoundly impacted control of many infectious diseases such as measles and smallpox because of the ability of vaccination campaigns to maintain long-term herd immunity and, hence, indirect protection of the unvaccinated. In the case of human influenza, such potential benefits of mass vaccination have so far proved elusive. The central difficulty is a considerable viral capacity for immune escape; new pandemic variants, as well as viral escape mutants in seasonal influenza, compromise the buildup of herd immunity from natural infection or deployment of current vaccines. Consequently, most current influenza vaccination programs focus mainly on protection of specific risk groups, rather than mass prophylactic protection. Here, we use epidemiological models to show that emerging vaccine technologies, aimed at broad-spectrum protection, could qualitatively alter this picture. We demonstrate that sustained immunization with such vaccines could--through potentially lowering transmission rates and improving herd immunity--significantly moderate both influenza pandemic and seasonal epidemics. More subtly, phylodynamic models indicate that widespread cross-protective immunization could slow the antigenic evolution of seasonal influenza; these effects have profound implications for a transition to mass vaccination strategies against human influenza, and for the management of antigenically variable viruses in general.     

Vaccines against poverty

With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an exciting time for vaccines against poverty, that is, vaccines against diseases that disproportionately affect low- and middle-income countries (LMICs). The Global Burden of Disease Study 2010 has helped better understand which vaccines are most needed. In 2012, US$1.3 billion was spent on research and development for new vaccines for neglected infectious diseases. However, the majority of this went to three diseases: HIV/AIDS, malaria, and tuberculosis, and not neglected diseases. Much of it went to basic research rather than development, with an ongoing decline in funding for product development partnerships. Further investment in vaccines against diarrheal diseases, hepatitis C, and group A Streptococcus could lead to a major health impact in LMICs, along with vaccines to prevent sepsis, particularly among mothers and neonates. The Advanced Market Commitment strategy of the Global Alliance for Vaccines and Immunisation (GAVI) Alliance is helping to implement vaccines against rotavirus and pneumococcus in LMICs, and the roll out of the MenAfriVac meningococcal A vaccine in the African Meningitis Belt represents a paradigm shift in vaccines against poverty: the development of a vaccine primarily targeted at LMICs. Global health vaccine institutes and increasing capacity of vaccine manufacturers in emerging economies are helping drive forward new vaccines for LMICs. Above all, partnership is needed between those developing and manufacturing LMIC vaccines and the scientists, health care professionals, and policy makers in LMICs where such vaccines will be implemented.Vaccination has made a greater impact on global health to date than any other medical intervention (1). As well as alleviating death and suffering, the widespread implementation of vaccines results in improved economic development (2). Much of the global benefit from vaccination has come through the delivery of vaccines to infants in low- and middle-income countries (LMICs) through the Expanded Programme on Immunization (EPI), which was introduced in 1974. The EPI has been key for the delivery of vaccines against diphtheria, tetanus, pertussis, measles, poliomyelitis, and tuberculosis to more than 80% of the world’s children (3) and is being used to roll out vaccines against Haemophilus influenzae b (Hib), rotavirus, and pneumococcus. The success of the EPI in LMICs has been underpinned by support from the Global Alliance for Vaccines and Immunisation (GAVI) Alliance, which was established in 2000 as a public-private partnership with a mission to improve global health through increased access to vaccines in low-income countries (4). Vaccination has stayed at the forefront of global health policy in the new millennium with United Nations Millennium development goals (MDG) 4 and 5, to reduce childhood mortality and improve maternal health (5), very much focused on infectious diseases. With considerable support of the Bill and Melinda Gates Foundation (BMGF), the 2010s were declared the Decade of Vaccines, with new funding pledged for vaccine research and development and for the delivery of vaccines to LIMCs at the 64th World Health Assembly in 2011 (6) and the endorsement of the Global Vaccine Action Plan (GVAP) (7) at the 65th World Health Assembly in 2012.