C. John Clements

Immunization of children at risk of infection with human immunodeficiency virus

This paper reviews the English language literature on the safety, immunogenicity and effectiveness in children infected with the human immunodeficiency virus (HIV) of vaccines currently recommended by WHO for use in national immunization programmes. Immunization is generally safe and beneficial for children infected with HIV, although HIV-induced immune suppression reduces the benefit compared with that obtained in HIV-uninfected children. However, serious complications can occur following immunization of severely immunocompromised children with bacillus Calmette-Gu rin (BCG) vaccine. The risk of serious complications attributable to yellow fever vaccine in HIV-infected persons has not been determined. WHO guidelines for immunizing children with HIV infection and infants born to HIV-infected women differ only slightly from the general guidelines. BCG and yellow fever vaccines should be withheld from symptomatic HIV-infected children. Only one serious complication (fatal pneumonia) has been attributed to measles vaccine administered to a severely immunocompromised adult. Although two HIV-infected infants have developed vaccine-associated paralytic poliomyelitis, several million infected children have been vaccinated and the evidence does not suggest that there is an increased risk. The benefits of measles and poliovirus vaccines far outweigh the potential risks in HIV-infected children. The policy of administering routine vaccines to all children, regardless of possible HIV exposure, has been very effective in obtaining high immunization coverage and control of preventable diseases. Any changes in this policy would have to be carefully examined for a potential negative impact on disease control programmes in many countries.

Using immunization delivery strategies to accelerate progress in Africa towards achieving the Millennium Development Goals

Integration of health services brings together common functions within and between organizations to solve common problems, developing a commitment to a shared vision and goals, and using common technologies and resources to achieve these goals. Integration has been the frustrated rally call of Primary Health Care for 30 years. This paper discusses the process of integrating child survival strategies and other heath services with immunization in Africa. Immunization is arguably the most successful health programme throughout the continent, making it the logical vehicle for add-on services. Strong health systems are the best way of delivering cost-effective child survival interventions in a most sustainable manner. But the reality in many African countries is that health systems have been weak for a number of reasons. Joining additional cost-effective child survival interventions on to immunization services may provide the needed boost. The unacceptably high childhood mortality in parts of Africa makes it the ideal location to undertake this exercise. The urgency to scale-up child survival interventions that have proven cost-effective is especially important if the Millennium Development Goals (MDGs) are to be met by 2015. Africa has more to loose than most in failing to scale up to meet these goals, bearing as it does the highest burden of childhood mortality in the world. But so far, prospects do not look good for achieving MDG-4 for the countries with the highest mortality rates. The timeliness of this initiative towards integration could not be better. In the last five years, countries in Africa have received massive injections of financial resources for polio eradication and measles control as well as additional funding for a range of immunization-strengthening activities and the introduction of new and under-utilized vaccines. While the data to support integration are limited, the information to hand suggests the effectiveness of the strategy. Where immunization performance is strong, immunization contacts may be excellent vehicles for additional interventions such as de-worming or Integrated Management of Childhood Illness (IMCI). But where an immunization service is struggling, adding another child survival intervention on to immunization might be the straw that breaks its back. Health managers have a wide range of options for adding on to immunization services, but the best choice will depend very much on local situations.

Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?

Since its widespread introduction, the hepatitis B vaccine has become an essential part of infant immunization programmes globally. The vaccine has been particularly important for countries where the incidence of hepatitis B virus-related hepatocellular carcinoma is high. Effective treatment options for individuals with chronic hepatitis B infection were limited until 1998 when lamivudine, the first nucleoside analogue drug, was introduced. As a single treatment agent, however, lamivudine has a significant drawback: it induces lamivudine-resistant hepatitis B virus strains that may pose a risk to the global hepatitis B immunization programme. Mutations associated with drug treatment can cause changes to the surface antigen protein, the precise part of the virus that the hepatitis B vaccine mimics. However, the emergence of antiviral drug-associated potential vaccine escape mutants (ADAP-VEMs) in treated patients does not necessarily pose a significant, imminent threat to the global hepatitis B immunization programme. Nonetheless, there is already evidence that current treatment regimens have resulted in the selection of stable ADAP-VEMs. Treatment is currently intended to prevent the long-term complications of hepatitis B virus infection, with little consideration given to potential adverse public health impacts. To address individual and public health concerns, trials are urgently needed to find the optimal combination of existing drugs that are effective but do not induce the emergence of ADAP-VEMs. This paper examines the mechanism of antiviral drug-selected changes in the portion of the viral genome that also affects the surface antigen, and explores their potential impact on current hepatitis B immunization programmes.

Mass Psychogenic Illness After Vaccination

When vaccines are administered to groups, the physical reactions of the recipients may be similar, causing a form of mass reaction, the mechanism for which is the same as that for mass reactions from other causes. These phenomena have been categorised as mass psychogenic illness (MPI), and have been defined as the collective occurrence of a constellation of symptoms suggestive of organic illness but without an identified cause in a group of people with shared beliefs about the cause of the symptom(s). A review of the literature shows that such outbreaks have been reported in differing cultural and environmental settings including developing and industrialised countries, in the work place, on public transport, in schools, and the military. The perceived threats have been against agents such as food poisoning, fire and toxic gases. Whatever the place or perceived threat, the response seems to be similar. The symptoms generally included headache, dizziness, weakness, and loss of consciousness.Once under way, MPIs are not easy to stop. Incidents reported in the literature show that they can quickly gather momentum and can be amplified by the press who disseminate information rapidly, escalating the events. Management of such mass events can be extremely difficult. Should the public health official in charge continue to try and determine the cause, or should this person call off the entire investigation? It is suggested here that once vaccines are identified as a probable cause of the phenomenon, a dismissive approach may actually be harmful. Unless the spokesperson has already earned a high level of trust, the public are not likely to be convinced easily that nothing was wrong with the vaccine until it has been tested.An increased awareness of MPIs on the part of organisers of future mass vaccination campaigns seems appropriate. Immunisation managers should be aware that mass immunisation campaigns could generate such mass reactions. It is therefore essential that surveillance/reporting systems for reporting adverse events be improved before such campaigns. A mass campaign using a smallpox vaccine should be accompanied by a surveillance system capable of distinguishing between multiple cases of conventionally understood vaccine reactions and outbreaks of mass psychogenic illness.

When science is not enough – a risk/benefit profile of thiomersal-containing vaccines

Without a preservative, such as thiomersal (known as thimerosal in the US), multi-dose liquid presentations of vaccine are vulnerable to bacteriological contamination that can result in death or serious illness of the recipient. Concerns about levels of mercury exposure from thiomersal-containing vaccines were first raised in the US during 1999 in the context of Hepatitis B vaccine for newborns. Since then, a large body of evidence from animal and epidemiological studies has accumulated on the safety of thiomersal. Ironically, these data have become largely irrelevant in wealthy countries, where mono-dose, thiomersal-free vaccines have been introduced as a precautionary measure in almost all childhood vaccines, in part related to residual public scepticism. In poor countries, multi-dose vials remain important for vaccine delivery. There is a real danger that this controversy may result in the loss to the world of thiomersal as a preservative, simply from popular pressure. In reality, it would be impossible to cease overnight using thiomersal and maintain the supply of vital vaccines. This paper reviews and summarises the data available from published studies on mercury toxicity, and thiomersal in vaccines in particular, that overwhelmingly indicate continued use of thiomersal is safe in those countries where it is most needed.

Vaccine presentations and delivery technologies – what does the future hold?

There is an urgent need to change the presentations and delivery technologies of current vaccines. Until recently, these factors had not been key criteria in the selection of vaccines for program use. Recent and current changes in the field of vaccines and their delivery lead the authors to postulate that a major paradigm shift will take place over the next decade to revolutionize vaccine presentation and delivery in national immunization programs. The programmatic needs for certain vaccine presentations will increasingly dictate elements of vaccine development and manufacture. Over the next decade, an inexorable drift towards firstly, single-dose preparations, and secondly, delivery technologies other than the conventional needle and syringes is anticipated. A unified system capable of delivering multiple antigens as a single dose is urgently needed; however, changing the status quo of vaccine manufacture is not easy. The market predominantly produces vaccines delivered by needle and syringe. Profits for manufacturers from sales to developing countries are marginal at best, and there is little financial incentive to change. Global leaders will need to take bold decisions and begin demanding vaccines which have a presentation that lends them to safer, more practical delivery systems. If a strong enough case can be made to restructure the vaccine manufacturing industry, either through market forces, global bodies, such as the World Health Organization and the United Nations Children’s Fund, or both, a dramatic change could be brought about that will make vaccine delivery simpler and safer. A globally coordinated approach to funding research and the introduction of a multiple-antigen, single-dose delivery system is urgently needed. The needs are clear, and this review argues that if the case is presented strongly enough, the resources will be found.

Implementing a birth dose of hepatitis B vaccine for home deliveries in Africa—Too soon?

Despite the recommendation of the World Health Organization (WHO) to provide the first hepatitis B vaccine dose at birth (within 24h), there are epidemiological, economic and logistical reasons why this may not be the best approach for home births in Africa. The WHO policy presupposes that the epidemiology of hepatitis B infection in Africa is similar to the rest of the world and that the organizational, infrastructural and financial support is adequate. While babies born in health facilities may be relatively easy to immunize at birth, health systems and infrastructures in many resource-poor countries in Africa would be severely challenged, if required to reach home deliveries within 24h of birth.

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.

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 prefilled 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.

Measles in Papua New Guinea: An age-specific serological survey

We aimed to determine the proportion of the population in Madang (Papua New Guinea) immune to measles infection by age groups, with respect to immunization status and study location, using dried blood sampling technology. We performed a prospective cross-sectional sero-survey. Population immunity against measles was sub-optimal (77%) and reported measles vaccine coverage in children <10 years of age was low (41%). The urban population was more susceptible to measles infection, compared with the rural population (66% vs 79% immune, aOR=0.6, p=0.05). Sero-conversion and long term protection rates appeared to be higher when at least one dose of vaccine was provided at or after 12 months of age (84% vs 59%, aOR=4.3, p=0.004). Such a dose is, however, not currently prescribed by the national immunization schedule.