Special Theme ± Immunization Safety Public Health Classics This section looks back to some of the ground-breaking contributions to public health, reproducing them in their original form and adding a commentary on their significance from a modern-day perspective. To complement this month's theme of the Bulletin, Sir Gustav Nossal reviews the 1965 paper by Louise W. Rauh & Rosemary Schmidt on measles immunization. The original paper is reproduced by permission of the American Medical Association. Inactivated measles vaccine and the risk of adverse events G.J.V. Nossal1 The article by Rauh & Schmidt, reproduced here as a tion. In many countries, the second dose of measles Public Health Classic and originally published in 1965 vaccine is not given until the teenage years, yet (1), raises a number of important points with respect immunized children do appear to be protected to both strategies for immunization and adverse despite only having received one dose. An attack of events of vaccines. In putting this material into measles probably confers lifelong immunity. It is context, we must recall that measles is a disease of difficult to escape the conclusion that this must mean considerable public health importance. While in the some type of persistent antigenic stimulation of the industrialized world the case fatality rate of measles immune system, perhaps via measles virus antigens is quite low (varying from 1 in 3000 to 1 in 10 000, leaking out from cells in which the measles virus has depending largely on age), measles is an extremely gone underground. Were persistence of immunity to serious disease in developing countries where the be the result of repeated environmental restimulation case fatality rate can be 2% or 3%. This high mortality of the immune system, one might have expected an is due at least in part to the severely immunosupres- equivalent degree of environmental boosting among sive effects of the disease. Present high level efforts at the recipients of killed virus vaccine, but that was not measles control, and in some countries actual measles observed. elimination, thus represent interventions of very The second point to note is that most of the great importance. children who got measles after immunization with The first point to make is to note the highly killed vaccine had a modified form of attack temporary nature of the immune response to the representing mild disease only in approximately killed virus vaccine. Three doses of vaccine given a four-fifths of the cases. However, about a fifth of month apart actually achieved 100% seroconversion, the children developed fairly severe disease with butonlyaquarterofthesechildrenstillhad atypical manifestations. Prominent features were neutralizing antibodies a year later. This contrasts severe rash with purpuric lesions and evidence of an markedly with the much better persistence (usually allergic reaction such as urticaria. This suggests an for many years)of antibodies following administra- allergic reaction perhaps triggered by the virus tion of the live attenuated vaccine. Furthermore, 98% combining with antibodies present in larger amounts of children responded to booster injections of killed than normal because the virus produced a type of vaccine given a year later, but only 69% of children endogenous booster dose to the immune system. were still seropositive nine months after the booster However, a confounding factor was the possibility injections. This relatively poor persistence of anti- that some of these allergic reactions could have been bodies was clinically significant, because 43% of due to penicillin. exposed children actually developed clinical measles, Allergic reactions to vaccines are not common, i.e. the lack of antibodies as detected was accom- but do undoubtedly occur. Allergic manifestations panied by susceptibility to disease. due to the intentional administration of antigen in the This raises the question of why an attack of presence of prior active antibody formation to the measles or a dose of the live attenuated measles antigen in question is well known, as in the case of a vaccine manages to create such long-lasting protec- second administration of horse serum, e.g. in the old way of attempting to prevent tetanus. The creation of soluble antigen±antibody complexes during a normal attack of measles may well be the mechanism for the 1 Professor Emeritus, Department of Pathology, The University rash and for some complications. The question of of Melbourne, Victoria 3010, Australia. whether some alteration in the balance of antigen and Ref. No. 0454 224 # World Health Organization 2000 Bulletin of the World Health Organization, 2000, 78 (2) Inactivated measles vaccine and the risk of adverse events antibody was at the root of the severe petechial rash in abnormal reactions and thus the company promoting these atypical measles cases is more moot. the vaccine would not have proceeded to phase III There is one lesson we must draw from the trials. It is of course possible that a company article by Rauh & Schmidt. Any and every claimed promoting such a vaccine would today use a more adverse effect from immunization needs to be powerful adjuvant, in which case it is hard to predict thoroughly investigated. Given that vaccines repre- what the results would have been. Overall, current sent one of the very few interventions that we make licensing processes with their very heavy emphasis in healthy individuals, safety must rightly be regarded on vaccine quality and safety allow us to detect and as a paramount issue. There will be situations such as identify problems relatively quickly. This minimizes these atypical cases where the pathogenesis is unclear. the chances of negative effects although, of course, it Each claimed adverse event will have to be examined cannot eliminate them altogether. For this reason, on a case-by-case basis with mature expert judgement post-licensing surveillance remains extremely im- being required to adjudicate on the validity of the portant. Altogether, modern communications and claim, and on the wisdom or otherwise of proceeding the collaborative relationships that arise within with the vaccine in question. multicentre trials help to minimize negative out- By today's criteria, it is highly unlikely that the comes and frequently lead to quicker identification inactivated measles vaccine would have been of problems. It also has to be said that the major licensed. Regulatory authorities would note the regulatory bodies adopt an interactive stance with relatively poor immune response and particularly companies, and can actually be very helpful if the rapid decline in antibody titres. In view of the difficulties arise. n relatively small number of patients that gave the relatively high incidence of atypical measles with 1. Rauh LW, Schmidt R. Measles immunization with killed virus undesired allergic features, it is quite possible that a vaccine. American Journal of Diseases of Children, 1965, phase II trial performed today would have shown the 109: 232±237. Bulletin of the World Health Organization, 2000, 78 (2) 225.