Editorial: Adverse reactions to vaccines in the tropics

The use of Edmonson Zagreb high-dose measles vaccine at the age of 4–6 months was associated with an excess mortality in girls during their second year of life (Expanded Programme on Immunization 1992). This extraordinary phenomenon has not been explained, although the replication of the finding in Guinea Bissau, Senegal, Haiti and Sudan leaves no room for doubt that it happened. The point that we wish to make here concerns how it was detected. The first observations were made in Bissau and in Senegal. In both these situations the trials using this vaccine were carried out in populations under long-term demographic surveillance. It was because of this that mortality could be examined. The standard use of ‘oral post mortems’, whereby the usual carer of the child was interviewed to determine the likely cause of death, provided the information that these deaths were not due to one specific cause of death but the broad range of causes normally found in children of that age. Would this quite unexpected adverse event have been detected without the special surveillance? The answer is probably no. This is especially so since the causes of death were the usual ones for that population. If there had been an unusual syndrome then routine health services might have detected the abnormality. This is old news since it all became clear in the early 1990s. However, adverse reactions are back on the agenda for the tropics because of rotavirus vaccine. Rotavirus is a major cause of morbidity and mortality in most of the tropics. Therefore the development of a multivalent oral vaccine that was highly effective led to the expectation that it would soon be integrated into the expanded programme on immunization. Unfortunately before many trials of this vaccine in the tropics could get underway, the postlicensure experience in the USA has unravelled those hopes. Routine surveillance using record linkage suggested an excess of cases of intussusception amongst recipients of the rotavirus vaccine (Anonymous 1999). Subsequent case control studies have confirmed this association. Needless to say this rapidly led to the withdrawal of the vaccine and suspension of all ongoing studies in the tropics. The rapid development of new rotavirus vaccines is now urgently required. However, studies of such vaccines will now need to include the assessment of the potential risk of intussusception. This is all well and good in countries with highly sophisticated health services, but how many countries in the tropics could set up surveillance for intussusception (not to mention how big any trial would need to be to assess it)? What is clear is that the potential benefits from rotavirus vaccine far outweigh as rare an adverse event as intussusception is likely to be. The EZ story makes the point that there needs to be a research framework for some adverse reactions to be detected. The rotavirus tale illustrates that adverse reactions in the USA may obstruct the use of highly valuable vaccines in the tropics unless there are mechanisms in place to show the true risk/benefit in the tropics. Currently vaccine trials in the tropics look at short-term adverse events in phase two immunogenicity studies. These are too small to detect anything but very common problems. In phase three trials mortality is usually measured – at least over the two to three-year period of the trial – but cause-specific morbidity beyond the specific endpoints of the trial is rarely available. In this situation where the trial participants number between one and 10 thousand, any excess mortality would have to be considerable to be detected. So essentially we do not have mechanisms for the detection of adverse reactions to routine vaccination in the tropics. Does that matter? The EZ and rotavirus episodes suggest it does matter from a practical point of view. However, there is also a strong biological argument that adverse reactions might differ in the tropics. Adverse reactions arise because of a pathological immunological response to the vaccine. A number of mechanisms for this have been proposed. Whatever mechanisms are involved, it is clear that the immune system in the tropics differs from that elsewhere. The burden of infectious challenge early in life, malnutrition and potential exposure to immune modulators such as malaria, UV radiation and pesticides all affect the developing immune system. In addition the risk of an injection carrying another infection either through a contaminated needle or syringe, or actually through contaminated vaccine, is likely to be very different in less developed countries. Thus the pattern of adverse reactions seen in western countries can not be extrapolated directly to the tropics. We need systems to assess them that are not predicated on what is known and which can pick up the unexpected. How might this be done? For most of the tropics we have no routine data collection systems for morbidity or cause specific mortality at the individual level. For many there is TMIH552