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Development of new vaccines
A number of new vaccines with major potential for controlling infectious diseases have just been licensed or are at advanced stages of development. Among the illnesses targeted are rotavirus diarrhoea, pneumococcal disease, and cervical cancer (as caused by human papillomavirus), which together kill more than a million people each year, most of them in developing countries. In addition to these efforts against diseases of global importance, progress is being made on a vaccine for the regional menace posed by meningococcal meningitis serogroup A, which causes frequent epidemics and high rates of death and disability in African countries south of the Sahara.
These advanced candidate vaccines are the focus of the information provided below. However, it should be noted that continuing, intensive efforts are under way to develop effective vaccines for AIDS, malaria, tuberculosis, dengue, leishmaniasis, and enteric diseases, among others and to adapt new technologies to improved formulation and delivery.
Vaccine development proceeds through discovery, process engineering, toxicology and animal studies to human Phase I, II, and III trials. The process can take more than 10 years, depending on the disease. The human trials focus initially on safety, involving small groups of people (I); then progress to moderate-sized "target" populations (persons close to the age and other characteristics for whom the vaccine is intended) to determine both safety and the stimulation of immune response (II); and finally to large target populations to establish whether a vaccine actually prevents a disease as intended (efficacy) (III).
The current situation of a number of new vaccines is described below:
Acute diarrhoea is responsible for nearly 1.9 million deaths per year in children under age five. Rotavirus is responsible for as much as one fourth of these casualties, almost all of which occur in developing countries.
Status of vaccine development: RotaRix, a vaccine developed by GlaxoSmithKline (GSK), against rotavirus diarrhoea is now licensed in many countries. In addition to being available on the private market in these countries, it has now been introduced in the public sector immunization programmes of Brazil, El Salvador, Mexico, Panama and Venezuela. . A Phase III trial is also under way in South Africa and Malawi.
RotaTeq, a rotavirus diarrhoea vaccine developed by Merck, is licensed and has been introduced in the immunization programme of Nicaragua. Trials in Asia and Africa are likely to start in 2007. Rotavirus vaccines in earlier stages of development include a vaccine sponsored by the United States National Institutes of Health; a neonatal vaccine developed by an Indian-United States consortium; and an Australian neonatal vaccine. They may provide an alternative option to today's products.
Challenges: A vaccine must be effective against numerous rotavirus strains (serotypes), including those prominent in developing countries. Large, stringent safety trials are necessary because an earlier, unrelated rotavirus vaccine appeared to cause, in rare cases, a serious complication called intussusception, a reverse telescoping of one part of the intestine into another. These vaccines, since they are live, oral ones, must be shown not to interfere with oral polio vaccine and must be efficacious. Even more importantly, they must be shown to be safe in general, and in HIV-infected children in particular. Price will also be an issue for large-scale introduction.
Prospects: Rotavirus vaccines are starting to be used in developing countries, but information on their effectiveness in Africa and Asia will not be available until 2008. They are expected to be ready for widespread use in immunization programmes in Africa and Asia by 2009.
Acute lower respiratory infections are responsible for close to two million deaths per year and a large proportion of these are caused by Streptococcus pneumoniae (pneumococcus). A study in The Gambia has indicated that more than one third of these deaths might be caused by pneumococcus. Most victims are children in developing countries. Pneumococcus also causes other serious illnesses such as meningitis and septicaemia. Pneumonia deaths far outnumber deaths from meningitis. Nonetheless, in non-epidemic situations, Streptococcus pneumoniae is a major cause of meningitis fatalities in sub-Saharan Africa; of those who develop pneumococcal meningitis, 40-75 % either die or are permanently disabled. Children infected with HIV/AIDS are 20-40 times more likely to contract pneumococcal disease than children without HIV/AIDS.
Status of vaccine development: A seven-valent conjugate vaccine called Prevnar (or Prevenar) is designed to act against seven strains of pneumococcal disease. It has been developed by Wyeth Vaccines and is licensed in the United States and over 70 other countries, but does not include two serotypes (types 1 and 5) that cause a high percentage of pneumococcal illness in developing countries. (Conjugate vaccines, which have proven to be highly effective, are made by linking purified polysaccharides - complex sugars - from the coat of a disease-causing bacterium to a protein "carrier.") In the United States, use of this vaccine has led to a dramatic decline in rates of pneumococcal disease, not only in immunized children, but also in the un-immunized population through reduced transmission. Wyeth Vaccines has also completed evaluation of a nine-valent conjugate vaccine, including serotypes 1 and 5. A Phase III trial of the vaccine involving 40 000 people was completed in South Africa in 2002, and a Phase III trial with 17 437 subjects was concluded in the Gambia in 2004. In the South African trial, the vaccine reduced invasive disease caused by the relevant serotypes by 83% in HIV-uninfected children and by 65% in HIV-infected children. Results from The Gambia trial show the vaccine was 77% effective in preventing infections caused by the relevant serotypes; that it resulted in 37% fewer cases of pneumonia (as confirmed by chest X-ray) as compared with a control group; and that recipients experienced a 16% reduction in overall mortality. Vaccines containing ten or thirteen serotypes are expected to be submitted for licensure within the next few years. In addition, developing country vaccine manufacturers have initiated development of conjugate vaccines. Vaccines based on common protein antigens of pneumococcus are also in the pipeline.
Challenges: It can be difficult to establish the extent of pneumococcal disease as developing countries often lack the laboratory facilities, expertise, and resources to do so. As a result, public health decision-makers are often unaware of the prevalence of the disease and of the toll it exacts in death and disability. Because of the scarcity of data from developing countries, there is concern over the appropriate serotype valency for developing countries. Concerns remain - although results to date are encouraging - that prevention of some serotypes of pneumococcal disease may be offset by an increase in incidence of disease due to other serotypes. The price of the vaccine, although still to be set for developing countries, may be too high for them to afford without special financing arrangements. A new innovative financial initiative (AMC - Advanced Market Commitment) may soon provide financing for the purchase of pneumococcal vaccine.
Prospects: A vaccine providing effective protection against pneumococcal disease for young children in developing countries could be introduced in a few countries, provided adequate supply and financial help are arranged.
Human papillomavirus (HPV)
Sexually transmitted HPV is the major cause of cervical cancer, the most common cause of cancer deaths among women in developing countries. About 500 000 cases occur each year, 80% of them in developing countries. Cervical cancer kills some 240 000 women annually.
Status of vaccine development: Gardasil, an HPV vaccine recently licensed by Merck, covers four types of HPV, including the cancer-causing types 16 and 18 and types 6 and 11 for non-cancerous genital warts. A second vaccine, developed by GSK, covers HPV types 16 and 18 alone and is expected to be licensed in 2007.
Challenges: HPV types 16 and 18 cause around 70% of HPV cervical cancers globally, but the vaccines in development will not cover the 30% of cancers attributed to other HPV types. Because these other types are numerous and individually only contribute a small percentage, significantly expanding vaccine coverage against them may present technical challenges for manufacturers. The duration of the immunity conferred by the vaccines is not yet known, and only time and follow up studies will provide this critical information.. Other clinical studies are planned that will look at alternative schedules and possibly lowering the age of vaccination. Because HPV is spread by sexual contact, and the high-risk years for infection are roughly from ages 18 to 25, the best subjects for vaccination will likely be pre-adolescents or adolescents, unlike for traditional vaccination programmes, which are aimed mostly at infants and pregnant women. Access to the vaccines is likely to be an issue in developing countries due to limited resources for the implementation of vaccination programmes.
Prospects: Discussions are ongoing about collecting the necessary data for introducing the vaccines into developing countries. Their systematic use in developing countries may well depend on local epidemiology, acceptability, financial resources, and the feasibility of vaccinating adolescents. There is also an immediate need to put in place an information/communication strategy, at all levels and for WHO to develop a position on the future use of this vaccine and the related public health opportunities it can offer.
Meningococcal meningitis A (Men A)
The African "meningitis belt" - which includes all or part of 21 countries stretching south of the Sahara desert from Senegal to Ethiopia - is the site of frequent epidemics, usually caused by serogroup A meningitis. Over the past decade more than 700 000 cases have been reported. Roughly 10-20 % of persons infected die, and one out of five survivors is likely to suffer from a permanent disability such as hearing loss, mental retardation, or paralysis. The rate of meningitis epidemics in the region has increased in recent years.
Status of vaccine development: Polysaccharide vaccines (vaccines made from complex sugars taken from the outer coats of the Men bacterium) are currently in use, but are not very effective at protecting young children, do not create long-lasting immunity, and do not confer a "herd effect" - that is, do not prevent spread of the disease in non-vaccinated people through reduction of the carriage of the infectious agent by vaccinated people during epidemics. Because of these shortcomings, immunization with polysaccharide vaccines is usually undertaken only after the onset of an epidemic.
To provide greater and more efficient protection, a public-private effort called the Meningitis Vaccine Project (MVP) is developing a Men A conjugate vaccine. This vaccine is intended to have long-lasting effect, to create immunity in infants, and to allow protection to be conferred in advance through mass immunization programmes. Toxicology studies and animal studies have been successfully completed, and the animal studies suggest the conjugate vaccine is highly immunogenic - that is, stimulates high levels of antibodies against Men A infection. Phase I trials were conducted in India and Phase II trials are ongoing in Mali and The Gambia . Recruitment has been completed and preliminary results are expected in early 2007. Phase II and III trials are being prepared in the same sites, in addition to in Ethiopia and Senegal. A Phase II infant study is planned in Ghana.
Other conjugate vaccines, including a heptavalent vaccine (DTP Hep B Hib) covering serogroups A, and C, are being developed by the private sector; and a tetravalent vaccine has recently been licensed by Sanofi-Pasteur in the United States and Canada.
Challenges: Other meningococcal meningitis strains are circulating in Africa which will not be controlled by a vaccine for serogroup A. One strain, referred to as W135, has caused epidemics in Burkina Faso and a small outbreak serogroup X has recently been reported in Niger . This points out to the continued need for an strengthened surveillance in the countries of the meningitis belt.
Prospects: A low-priced (around US$ 0.40 per dose) conjugate vaccine for Men A may be ready for widespread use in the African meningitis belt by 2008 or 2009. In the meantime, sustainable funding, programmatic and delivery mechanisms need to be put in place in the belt countries to prepare the introduction and future use. A heptavalent vaccine will also be available (expected price US$ 4.50 per dose) in the same time frame,; it will protect against diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type B and meningitis serogroups A and C.
WHO Initiative for Vaccine Research (IVR)
The WHO Initiative for Vaccine Research was established in 2001 to streamline the various vaccine research and development projects being carried out by different departments of WHO (including the Special Programme for Research and Training in Tropical Diseases: TDR) and UNAIDS. IVR is an international team of scientists, managers, and technical experts whose task is to facilitate the development of vaccines against infectious diseases of major public health importance, to improve existing immunization technologies, and to ensure that these advances are made available to the people who need them the most. IVR will achieve these objectives using a three-pronged approach:
Sources: US Department of Health; The World Health Organization