Commentary: Surveillance of Reactions to Biologicals

Commentary: Surveillance of Reactions to Biologicals MHARLOTE A. HANNIK Side effects after prophylactic vaccination are a delicate subject. If there is a high incidence of an infectious disease and a newly developed vaccine against this disease becomes available, the public is pn- marnly interested in the protective activity of the vaccine, and side reactions are accepted, as long as they are less severe than the disease. This is the best situation in which to start a study of side reactions. Each analysis of protec- tive activity of a newly developed vaccine in the field should be combined with a study on its reactogenicity. If, however, the disease is under control and vaccination is performed routinely in order to continue the existing favourable epidemio- logical situation, then the population is less in- clined to accept side reactions. A good example is the vaccination against pertussis. Twenty years ago hlie efficacy of the pertussis vaccine had been proven beyond doubt (1 and 2). Nowadays vaccines which give excellent protection are available, but several countries have recently abandoned pertussis vaccination because of the side reactions. In this situation a study to assess the reactogeni- city of pertussis vaccine will be very difficult. Parents wlho are currently wniling to have their child vaccinated might withdraw their consent when they are confronted with a study on side reactions. Therefore. the first factor to take in- to consideration when planning a study on side effects is the epidemiological situation in a country and the psychological effects it lhas on the population. The Netherlands experienced a time with high pertussis mortality, but systematic vac- cination of infants reduced it. At the end of 1962, with the introduction of DPT-Polio vac- cine, it was decided to pay particular attention to side reactions because the mortality of the disease was zero, but some untoward reactions were reported. The simplest way to collect certain data is through a questionnaire. In addition to infor- mation, one may also get the personal view of the addressee, the parents, or the doctor. The complaints of the mother are influenced by her anxiety. Sometimes the child's crying makes her nervous; at another time she may accept a really serious situation but panics when the child refuses a feeding. A child with a temperature of 38°C is ill and shows signs of what is called in my country "general malaise." The diagnosis of this malaise is subjective. If, however. a fully documented case history is made of each reaction, other clinicians may agree. Therefore, each mother with a child who might have had a severe reaction after DPI- Polio vaccination was visited personally, and a complete case history was made of each re- ported side reaction. When the differeit reactions which might occur were known, a study was started in one province to obtain information about their frequency. After some years it became evident that the most reliable reporting came from one town. the Hague and, in particular, from one baby clinic in the Hague. This study on such major reactions as shock and convulsions oc- Paediatrician. Head of the Bureau ofProducts.Vational Institute ofPublic Health Antonie man Leeuwenkoekcaan 9, Postbox 1, Bilihoreen, The PiVetherlanads. 163 CA.Hanik curring up to 3 days after DPT-Polio vaccina- tion revealed a frequency which was at the same time surprising and alarming (3), as shown in Figure 1. This frequency was judged not to be ac- ceptable; hovr,ve did not want to abandon pertussis vaccliitibn. Therefore, the amount of pertussis antiau added to the DPT-Polio vac- cine was reduced, so that the final concentra- tion per human 4ose was 10 IU instead of 16. However, the potency of the final vaccine still meets the potency requirements of WHO of 4 IU per hunun dose. This vaccine has now been in regular use f9j, ver one year, and during this period no senous side reactions have been re- ported neither 4'rom the baby-clinic in the Hague nor from the rest of the country. The conclusion is that field studies on the reactogenicity 9f a vaccine should at least ini- tially be confined to small geographic areas from which reliable information can be ob- tained. The quaUty of data is much more im- portant than the quantity. However favoqqble this situation is now, it should be stressd4 that the mechanism of reac- tions after pertusia vaccination is still unsolved. There is no objective criterion to measure the reactogenicity of different vaccines in man, nor has a relationship been established of the toxi- city of different vaccines for animal and man. In order to obtain an objective criterion in man, a study was set up in that baby-clinic in the Hague. I now wat to give you the experience obtained during that study on untoward reac- tions after DPT-Polio vaccination in which both a venous puncture and a heel puncture had to be performed. Input First, I fully informed each mother with a child who met the cnrteria for inclusion in the study about why. the study was done, that her baby was to be, vpcinated with the normal routinely used DPT-Polio vaccine, and further, that it was not an experiment but a controlled application. Then she was told how a venous puncture was to be performed and that-in case the first attempt was not successful-no second one would be made. Thereafter the mother was given all opportunity for questions. If she hesi- tated with her decision, she was never over- ruled. If the mother was considering participation, a program for vaccination, clinical control, and bloodsampling was agreed upon; then she went home with her child still unvaccinated and a timetable for the next day. Therefore, the parents had ample time to make their final de- cision. The conversation with the mother was carried on in the baby-clinic in the presence of the nurse who was to assist the next day. Al- though no signature was asked, this procedure was considered as an informed consent proce- dure. The mother could refuse directly or after- wards by telephone or just not re-appear the next day. Output The advantages of this time-consuming intro- duction were a personal relationship with the mother and a positive attitude of the parents towards participation. Refusal was exceptional. More than half of the fathers were present at the blood sampling. They showed much interest in the results. Several fathers even took a day off from work in order to be present. There were no rumours, no decline of the acceptance rate of vaccination in the baby-clinic, and we never reached the local papers. Results of the Study Two cnrteria were studied. The first criterion was the temperature 8 hours after vaccination. This simple information, easily obtained proved to be /ery reliable (Fig. 2). There is a statistically significant difference in temperature 8 hours after vaccination with the DPT-Polio vaccine containing 16 IU and the vaccine with the reduced pertussis component. There was no difference in temperature in children vaccinated with DT-Polio vaccine and nonvaccinated children. A second criterion was the plasma-insulin level at the same time, 8 hours after vaccination (Fig. 3). There is a slight but sipiflcant elevation of 164 Commentay: Suwiusce of Rincdoa to Bido4cUIs 165 Figure 1 FrSuency of Shod and Convulsion afte DPT-Poliovccination Period of Estimated number Number of reactions obevation vaccinated children Shock Convlsion 1970-1974 The Hague 2B,000 8 - 1: 3,500 13 -I1: 2,150 1969-1974 Z. Hollbnd 190,000 11 - 1: 17,270 6 - : 31.660 Figure 2 __ - _ __Tm tue in °Ca H s aftw Vac_in_t_on Vaccine Number Mean temperature Statistical test result' DPT-polio-16 11 38.3 significant DPTIpolio-10 15 38.1 J significant DT-polio 9 37A 1 not significant control 8 3/.4 J aStudent's tet, onided lwel of significance 5%. Figure 3 Plam Insulin Le in *AJ/ML, 8 Hours afte Vacinatin Vaccine Number Mean Level Statistical test resulta DPT-polio-1B 14 13.5 not significant DPT.polio-10 18 8.9 significant DT-pollo 14 6.5 1 not significant control 10 7.1 J aStudentes tst, one-sided lel of significance 5%. the plasma-insulin level 8 hours after vaccina- don with the DPT-Polio vaccine containing 16 1U. The DT-Polio group does not differ from the control group; the insulin level of children vac- cinated with the DPTPolio vaccine with the re- duced pertussis component lies in the middle. It does not differ significantly from the level in the group vaccinated with the 16 IU DPI-Polio vaccine or from the control group. CONCLUSION It will be clear to you that I am not in favour of large comprehensive surveys of side reactions after vaccination. I do prefer initial small studies, taking into consideration the epi- demiological situation in a country. The first requirement of each study should be informed parental consent; the first pursuit should be to establish objective criteria. Refenes 1. Medical Research Council: Vaccination against whooping-cough: Relation between protection in cildren and results of laboratory tests. Bxit. Med. J., 2: 454462 (19S6). 2. Medical Research Council: Vaccination against whooping-cough: Final report. Brit. Med. J., 1: 994-1000 (1959). 3. Hannik, Ch.A.: Report on an informal consulta- tion on immunintion against whooping-cough. WHOIBAC/75.1: 22 (1975).