Breaking new ground--are changes in immunization services needed for the introduction of future HIV/AIDS vaccines and other new vaccines targeted at adolescents?

A safe, effective and accessible preventive vaccine is our best long-term hope for the control of the HIV/AIDS pandemic. Once the first generation of HIV vaccines are developed, many questions remain unanswered regarding their administration. For instance, which vaccines should be given to whom at what age and how many doses? We argue that pre- and early-adolescents will be one of the main target groups for future HIV vaccines, that is, before the age of exposure to the virus. Historically, immunization has mainly focused on infants. Indeed, vaccines have only occasionally been systematically targeted at adolescents, even in industrialized countries. Delivering vaccines to pre-adolescents and adolescents in developing countries would, to a great extent, be a new challenge. But it is not just HIV/AIDS vaccines that are coming down the pipeline. Herpes simplex type2 (HSV-2) and human papillomavirus (HPV) vaccines are also among the exciting candidate vaccines that may be the agents of change needed to encourage even the poorest countries to develop strategies for reaching adolescents with vaccines and other health services in the coming decade. Together, they may also provide the impetus for changing the paradigm for how vaccines are administered. Not only will more antigens be included in national immunization schedules, but the age of target groups will range much more widely than at present, encompassing older children, adolescents and young adults. While presenting major difficulties for delivery, these new ingredients also offer stimulating opportunities to completely rethink how vaccines are presented, administered and delivered. We predict that even the poorest countries will be looking to developing integrated, sustainable strategies for reaching pre-adolescents and adolescents with vaccines in the coming decade.

Misled and confused? Telling the public about MMR vaccine safety. Measles, mumps, and rubella.

The extraordinary events surrounding the measles, mumps, and rubella (MMR) vaccine in the United Kingdom have not only placed in jeopardy the use of this triple vaccine but have also spread concern to other parts of the world. Examination of the public's worry about MMR vaccine reveals they have been exposed to a range of conflicting views resulting in the feeling of having been misled about the safety of the vaccine. There are various groups and individuals who have legitimate roles in informing the public about such subjects. But is each one behaving in an ethically responsible way? And if confidence falters, vaccine coverage dips, and an outbreak of measles, mumps, or rubella ensues, who, if anyone, will stand and say "I misled them, I confused them, this is my responsibility"? We examine the ethical issues of each group with a voice in the debate about vaccine safety.

The global impact of vaccines containing aluminium adjuvants.

Immunization against childhood vaccine-preventable diseases has arguably had the greatest impact on the health of children of any public health intervention. Many of the vaccines used in the Expanded Programme on Immunization (EPI) have contained aluminium-based adjuvants. As such, these adjuvants have played a vital role in enabling the basic vaccines to be used effectively. DTP global supply is fragile and could easily be upset through the loss of even one major vaccine manufacturer. Non-aluminium adjuvants could not readily replace aluminium adjuvants. New generation vaccines will probably need new generation adjuvants. The impact of vaccines with adjuvants is discussed. Having provided decades of reliable, safe service in their relatively simple chemical formulations, adjuvants are likely to be with us, in one form or another, for the indefinite future.

Technologies to improve immunisation safety.

Ever since a vaccine was first used against smallpox, adverse events following immunisation have been reported. Adverse reactions may be caused by a fault in vaccine production, idiosyncratic responses or unsafe handling and vaccine administration practices. Technological advances that promise to bypass many of the dangers currently associated with vaccine administration are described. Plans for the next decade and beyond include developing injection-free systems for vaccine delivery that overcome the limitations of current immunisation programmes and help prevent programmatic mistakes. Also under development are new parenteral administration devices such as the auto-disable syringe and the mono-dose pre-filled device, and mucosal and transcutaneous immunisation systems. Training needs to be at the forefront of efforts to limit human error. Above all, there must be a willingness to respond to new climates and new technologies in order to ensure safe immunisation of children globally.

Thiomersal in vaccines: is removal warranted?

The mercury-based vaccine preservative thiomersal has come under scrutiny in recent months because of its presence in certain vaccines that provide the foundation of childhood immunisation schedules. Over the past decade new vaccines have been added to the recommended childhood schedule, and the relatively smaller bodyweight of infants has led to concern that the cumulative exposure of mercury from infant vaccines may exceed certain guidelines for the human consumption of mercury. In the US, government agencies and professional societies have recently recommended that thiomersal be removed altogether from vaccines. Some involved in developing vaccine policy feel that the evidence to support these safety concerns has not risen to the level required for such a response. This apparent divergence of opinion has left healthcare professionals and the public with uncertainty about the potential health effects from low level exposure to thiomersal as well as the necessity of removing thiomersal from vaccines. At present, scientific investigation has not found conclusive evidence of harm from thiomersal in vaccines. As a precautionary measure, efforts are under way to remove or replace thiomersal from vaccines and providers should anticipate the availability of more vaccine products that are thiomersal-free over the coming years.

Ensuring vaccine safety in immunization programmes--a WHO perspective.

Ever since vaccines were firstly used against smallpox, adverse events following immunization have been reported. As immunization programmes expand to reach even the most remote communities in the poorest countries, it is likely that many more events will be temporally linked with vaccine administration. Furthermore, the profound shift in the general public and media interest in adverse events may lead to undue concerns and allegations which may ultimately jeopardize immunization programmes world-wide. While the health professional has understood this issue for some time, the public and the media have now also become all too aware of the significance of vaccine-related adverse events. The familiar vaccines, well-tested over decades, have not changed--but the perception regarding their safety has shifted. Claims outrageous or reasonable are being made against both the old and the newly-introduced vaccines. At the same time, the immunological and genetic revolution of the last decade may well bring to our notice some hypothetical risks that need to be addressed at pre-clinical level. WHO has been at the leading edge to guarantee vaccine safety for the last 30 years and will continue to do so. The Organization's plans for the next decade and beyond include the Safe Injection Global Network (SIGN), the development and introduction of safer technologies, and the prevention, early detection and management of AEFIs. The new technologies include needle-containing injection devices such as the autodisable syringe, as well as mucosal and transcutaneous immunization. Training will continue to be at the centre of WHO's efforts, limiting human error to a minimum. Mechanisms have been set in place to detect and respond to new and unforeseen events occurring. Above all, there is a willingness to respond to new climates and new technologies so that the Organization is in the best position to ensure safe immunization for all the world's children.

[Strategies for minimizing nosocomial transmission of measles]. / Estrategias para reducir a un mínimo la transmisión nosocomial del sarampión.

Because of the highly contagious nature of measles before the onset of rash, nosocomial transmission will remain a threat until the disease is eradicated. However, a number of strategies can minimize its nosocomial spread. It is therefore vital to maximize awareness among health care staff that an individual with measles can enter a health facility at any time and that a continual risk of the nosocomial transmission of measles exists. The present review makes two groups of recommendations: those which are generally applicable to all countries, and certain additional recommendations which may be suitable only for industrialized countries.

Alternative routes of measles immunization: a review.

Measles is one of the major causes of childhood mortality in developing countries, despite current prevention of over 2 million child deaths each year by measles vaccination programmes. New strategies, such as mass campaigns, and possibly new preparations of measles vaccines, may facilitate further progress in controlling the disease and improving the prospects for its ultimate eradication. To evaluate the potential for non-percutaneous routes of vaccine administration to improve control, we reviewed studies of serological responses to measles vaccine after intradermal, conjunctival, oral, aerosol and intranasal administration. The response to intradermal vaccination exceeded percutaneous results in only one of eight instances in five studies where such comparisons could be made, often producing substantially lower seroresponses. Further, intradermal administration using a needle and syringe is more difficult than subcutaneous vaccination. After oral administration of vaccine, less than 50% of children seroconverted in three small studies. Intranasal administration has not yet been studied extensively, but it may be susceptible to interference by upper respiratory infections. Seroconversion after conjunctival administration was very variable, and this route was difficult practically in young children. In infants below 9 months of age, aerosol administration of vaccine resulted in 80% or better seroresponse in seven of nine trials, with the Edmonston-Zagreb strain in standard titre doses consistently producing better results than the Schwarz strain. However, seroresponses after subcutaneous administration clearly exceeded those from aerosols of the same vaccine in four of six comparisons. Several trials noted practical difficulties in aerosol administration in young infants. In contrast, older seronegative children generally responded well to aerosol administration of vaccine (above 90% and often 100% seroresponse), regardless of vaccine strain and often with surprisingly low estimated retained doses. In each of three studies where it was possible to compare the same vaccines given percutaneously and by aerosol to seropositive children, better seroresponses followed aerosols. In older children, aerosols of the Edmonston-Zagreb strain also rather consistently provided better seroresponses than aerosols of the Schwarz strain, with the most notable differences in seropositive children. Thus, with the possible exception of very young infants, the aerosol route is promising and offers several theoretical and practical advantages as well. Further randomized trials should be conducted to evaluate comparative responses to aerosolized, intranasal, and subcutaneous vaccine, especially in those age ranges targeted for mass campaigns (most commonly 9 months to 15 years). The development of improved technology for aerosol delivery of measles vaccine would greatly advance the potential for wide scale use of this route, especially in mass campaigns in low income countries.

Strategies for minimizing nosocomial measles transmission.

As a result of the highly contagious nature of measles before the onset of rash, nosocomial transmission will remain a threat until the disease is eradicated. However, a number of strategies can minimize its nosocomial spread. It is therefore vital to maximize awareness among health care staff that an individual with measles can enter a health facility at any time and that a continual risk of the nosocomial transmission of measles exists. The present review makes two groups of recommendations: those which are generally applicable to all countries, and certain additional recommendations which may be suitable only for industrialized countries.

Clinical problems in measles case management.

Measles remains one of the leading causes of childhood morbidity and mortality in developing countries. The World Health Organization has identified effective case management as one of the specific strategies to reduce the burden of this disease. The purpose of this article is to review the aetiology, natural history, treatment and outcome of the common clinical problems associated with measles with a view to identifying possible deficiencies in case management. Complications such as pneumonia, diarrhoea, croup and malnutrition have been well defined in terms of their relative contribution to morbidity and mortality. However, there are few published data on the aetiology and natural history of these specific complications. Such data are crucial for rational case management strategies. Data on treatment of measles and its complications are limited and the role of antibiotic prophylaxis and therapy is unclear. The only specific research focus on case management during the last decade has been vitamin A therapy. There is a continuing need for community and hospital-based studies on the natural history of measles and its complications, the aetiology of these complications and intervention strategies that will improve measles case management.

Assessment and possible control of endemic measles in urban Nigeria.

BACKGROUND: Measles remains as a serious problem of infancy and childhood in the developing world, despite the availability of a vaccine. Increasing urbanization is changing patterns of endemicity. METHODS: A survey of measles in an urban area of Nigeria, using a rapid assessment approach, was carried out to characterize measles in this community. RESULTS: An annual incidence rate of 11.8% among under-fives was found, associated with an acute case fatality rate of 3.3%. This level of endemicity was two orders of magnitude greater than that suggested by official case reports. An endemic, rather than epidemic, pattern was found over the six-month period of the study. Vaccine efficacy was estimated at 26%. Risk factor analyses showed the major risks for measles to be clinic attendance in the month preceding disease, households with more than one mother, and having under-five siblings. Measles itself was the principal risk factor for malnutrition and against survival. CONCLUSIONS: Improved understanding of measles epidemiology and risk factors are prerequisites for effective control. Possible strategies should include vertical vaccination efforts in addition to routine programmes.

The epidemiology of measles: thirty years of vaccination.

Measles is a highly infectious disease which has a major impact on child survival, particularly in developing countries. The importance of understanding the epidemiology of this disease is underlined by its ability to change rapidly in the face of increasing immunization coverage. Much is still to be learned about measles epidemiology and the best strategies for administering measles vaccines, as well as about the biological mechanisms of action of measles vaccines. However, it is clear that tremendous progress can be made in preventing death and disease from measles with existing knowledge about the disease, and by using the presently available vaccines and applying well tried methods of treating cases. Research in the coming decade may provide improved strategies and more effective vaccines for use in immunization programmes.

Immunization of 6 and 9 month old infants with AIK-C, Edmonston-Zagreb, Leningrad-16 and Schwarz strains of measles vaccine.

BACKGROUND: Measles kills more than 1 million infants per year and is particularly lethal in infants < 1 year old in developing countries. Recent reports have suggested that measles vaccines of different strains and titre differ in their immunogenicity in young infants. We sought to identify strains and titres of measles vaccines which would be effective in 6 and 9 month old infants. METHODS: We conducted a randomized trial of AIK-C, Edmonston-Zagreb (EZ), Leningrad-16 and Schwarz strains of measles vaccine at different titres in 1202 6 month old and 1250 9 month old infants. Antibody levels were measured by haemagglutination inhibition assay. Seroconversion was defined as a change from seronegative to seropositive or a fourfold rise in titre above the expected level after antibody decay (assumed antibody half-life = 6 weeks). Chi-square tests were used to compare seroconversion rates and rates of adverse reactions among the groups. Comparison of geometric mean titres (GMT) was done by the Student's t-test. RESULTS: No severe or unusual adverse reactions occurred during the 6 weeks after vaccination. All strains induced high seroconversion rates in 9 month old infants. In 6 month olds, medium- and standard-titre AIK-C induced the highest rates of seroconversion. Antibody titres at 6 weeks after vaccination were highest in recipients of Schwartz vaccine and lowest for EZ vaccine recipients. CONCLUSIONS: Standard-titre AIK-C may be more effective than other measles vaccine strains for early measles immunization and should be evaluated further for efficacy, long-term immunogenicity, and long-term safety.

The relationship between dose and response of standard measles vaccines.

A considerable number of field trials have been published over the last 30 years, showing measles vaccines to be highly effective. Due to inconsistencies in methodology, comparisons between these studies have often been difficult with regard to the potencies used and the sero-response of vaccinated children. This article reviews key studies which have measured the response of children to different potencies of vaccine. The review concludes that increasing the titre of vaccine above log10 3.0 does not appear to improve vaccine efficacy. It is recommended that standard titre measles vaccine should be administered with a minimum potency of log10 3.0 TCID50 or PFU per dose at 9 months of age or later. This recommendation is endorsed by the Global Advisory Group and the Research and Development Group of the Expanded Programme on Immunization.

Two-dose measles vaccination schedules.

As measles continues to exact a high toll on infant mortality, particularly in developing countries, optimal strategies for the control of the disease are under discussion. As part of this debate, the place of 2-dose measles immunization schedules is reviewed regarding their potential as a strategy to improve measles control. To date, WHO has not recommended the use of a 2-dose schedule. A number of industrialized countries have already adopted a 2-dose schedule, often choosing to administer measles vaccine in the same injection as mumps and rubella vaccines. However, at present not enough is known about such schedules in developing countries to make global recommendations. Further research should include randomized controlled trials of early 2-dose schedules to investigate both technical and epidemiological issues such as the effect of blunting immunity and the duration of antibody. Long-term safety should be determined through studies of adequate size. Programmes already using 2-dose schedules are encouraged to evaluate their impact on disease incidence, cost, vaccine usage, and effect on coverage. Until further evaluation is complete, a high and timely coverage with one dose of measles vaccine in all areas remains the first priority for all immunization programmes.

PIP: Worldwide coverage of measles vaccine is about 80%, but many communities and countries have considerably lower coverage rates. WHO is concerned about measles occurring in infants between 6 and 12 months old, especially in densely populated African cities. Measles rarely occurs in infants under 6 months old, but the measles case fatality rate is greatest in the 1st year of life. WHO aims for an effective measles vaccine to be administered at 6 months old. A high titer vaccine appears to reduce survival among children receiving it. Some countries have reduced measles incidence by as much as 90% by achieving coverage levels greater than 90% with a single dose measles vaccine. Another method to prevent early measles cases and later vaccine failures is administration of the 1st dose around 6 months and a 2nd dose no earlier than 12 months. Measles vaccine policy in the US and some countries in Europe is routine 2-dose measles schedules: 1st dose between 12-19 months and 2nd dose at school entry. This schedule is appropriate in developed countries with good immunization coverage. Other countries schedule the 1st dose anywhere between 6-9 months and the 2nd dose between 12 months and 7 years. All mathematical models of the effects of 2-dose schedules indicate that 2-dose schedule are a great benefit. The literature shows that developing countries with high immunization coverage and well-managed immunization programs can effectively execute and sustain 2-dose measles schedules. Measles vaccination early in life sometimes results in a blunted antibody response. The 2-dose schedules are probably more expensive than 1-dose schedules and require more cold storage space. No field trials have looked at clinical efficacy of 2-dose measles schedules in developing countries. Ideal field trials would be randomized controlled trials. Demonstration projects can evaluate operational issues, e.g., dropout rates, cost, and vaccine usage. Case control studies can address technical and epidemiological issues.