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Brief Reports Indian Pediatrics 2002; 39:556-560 |
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Measles Vaccine Efficacy Evaluated by Case Reference Technique |
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A. Puri
The effectiveness of a vaccine to prevent disease effectively is termed as vaccine efficacy. It can be defined as a per cent reduction in disease incidence attributable to vaccination. Though potency is tested before distribution, there is a need to study the efficacy of vaccines under field conditions. Under UIP, many different immunization centers and vaccinators are involved. The success of vaccination performed under field conditions is more realistically assessed by measuring protection against the disease by epidemiological methods such as screening, outbreak, investigations, secondary attack rates in families or clusters, coverage survey methods in endemic areas and case control studies. This epidemiological approach has an additional merit of not requiring laboratory support. Because of the ease of carrying out this technique, it can be very useful, particularly when doubt is cast on effectiveness of the vaccination program because of occurrence of disease in vaccinated individuals. The problem becomes increasingly prominent as vaccine coverage rises since the proportion of cases of illness occurring in vaccinated persons will increase even though vaccinated efficacy remains constant. Lower than expected vaccine efficacy determination should stimulate more intense investigations to determine causes and take corrective action, if necessary(1). This study was done to evaluate the case reference method of vaccine efficacy calculation, under field conditions. Vaccine efficacy of measles vaccine calculated by the attack rates in the vaccinated and unvaccinated group was compared with the vaccine efficacy calculated by measles serology of the study subjects. Subjects and Methods This was a community based cross-sectional study conducted in the slum areas of Delhi. Thirty clusters of urban slums were identified using the standard WHO-30 cluster sampling technique in the zone chosen. The choice of this zone was governed by its close proximity to college campus and ease of conducting the study. The approximate number of jhuggies in this zone were 51,427. Against the name of each slum, the individual population of the slum was written. The individual population of a particular slum was arrived at by multiplying number of jhuggies in that slum by 5(2). The cumulative slum population of city zone was 2,57,135. Thirty clusters were identified in the above popu-lation using 30-cluster sampling technique(3). Seven measles vaccinated and seven measles unvaccinated children of the age group 12-35 months were selected randomly from each cluster, thus a total of 420 children were included in the study. Children who had received measles vaccination before the age of nine months and who had an attack of measles prior to vaccination were excluded from the study. Information regarding name, age and sex of the child, history of measles attack and age at measles attack in both vaccinated and unvaccinated group was recorded in a pre-designed and pre-tested performa. The study being community based and cross-sectional in design, only one visit was made to each house. Wherever possible, the reported vaccination status of the child was cross-checked with the documentary evidence of vaccination like hospital ticket/OPD slip, general practitioners prescription, and anganwadi record. In those children where mothers failed to produce any documentary evidence of vaccination, history of vaccination given by the mother was taken as evidence, if it was found that the child had also been immunized for other vaccine preventable diseases appropriate for his age (assuming mother had no bias in getting the child vaccinated against measles as she had got the child vaccinated for other VPD’s). Documentary evidence of vaccination was available in 51.4% of the vaccinated group. In the unvaccinated group, records were available in 47.6% of children and in the others the unvaccinated status of the children was also based on the mother’s history and could not be confirmed by any other method during the study. The inherent limitation of this community based study is that the records are either not available or misplaced at the time of the investigation/interview. The source of health care including the preventive services, viz. immunization was primarily by private practitioners, Anganwadis and NGOs. Other sources of immunization were health centers, government hospitals and other health agencies that gave immunizations by home visits. A case of measles was accepted if on interviewing the mother, it was established that the child had: (a) history of generalized maculopapular rash of three or more days duration; (b) history of fever of 38ºC or more (or "hot to touch" if not measured); and (c) Atleast one of these — "cough, cold or URI or conjunctivitis" present(4). History of measles attack was considered positive only if the clinical presentation reported by the mother satisfied the criteria laid by the WHO(4). Earlier experience has showed that the history given by parents regarding the past attack is fairly reliable(5-7). The design of the study being cross-sectional, only one visit was made to each house and an attempt was made to collect the capillary blood of every child in both vaccinated and unvaccinated group. The capillary blood was collected by pricking finger or toe or heel with help of sterile disposable needles using all aseptic precautions in 288 study subjects. The capillary blood was soaked on rectangular Whatman No. 3 filter paper with 20 mm disc, so that each disc was completely soaked with blood on both sides. The strips were dried at room temperature, labeled and stored at 2-8ºC in a slide box. Hemagglutination inhibition test was performed on each sample in the Microbiology Department of Maulana Azad Medical College, Delhi. Children with antibody titers <1:8 were taken as sero-negative and children with antibody titers >1:8 were taken as sero-positive. This cut-off was governed by other studies using HAI test for measles antibody levels(7-9). The data was analyzed using Epi-Info software. Results Overall attack rate in the study children was found to be 26.0%. The difference in the attack rates of the vaccinated and unvaccinated children (14.3% and 37.6%, respectively) was statistically significant. The mean age of occurrence of measles in the present study was 15.48 (±3.16) months. The mean age of measles attack in the vaccinated group was 17.96 (±3.40) months and it was 14.69 (±2.91) months in the unvaccinated group (p <0.001). The relative risk was calculated to be 2.6 indicating that an unvaccinated child is 2.6 times more prone to develop measles as compared to a vaccinated child. In the present study, the vaccine efficacy by case- reference method was 62% (95% CI: 46% - 73% ( Table I). Table I-Computation of Vaccine Efficacy from the Distribution of Measles Cases According to Their Vaccination Status
Figure in parenthesis shows percentages Vaccine efficacy = ARU - ARV/ ARU × 100 = 37.6 – 14.3 / 37.6 × 100 = 61.96 ~ 62% (95% CI:46% - 73%) where, VE = Vaccine efficacy ARU = Attack rate in unvaccinated ARV = Attack rate in vaccinated
Along with the field evaluation technique, laboratory methods were also utilized to determine the vaccine efficacy. For the purpose of the study, a dilution of 1.8 and above was taken as a protective titer. Out of 288 blood samples, 140 (48.61%) had protective antibodies against measles while 148 (51.39%) were sero-negative. In the vaccinated grop. 75.2% had protective HAI antibodies while in the unvaccinated group, 30.4% had protective HAI antibodies. The sero-negatives percentage in the vaccinated group was 24.8% while in the unvaccinated group it was 69.6 % Geometric Mean Titer (GMT) of the vaccinated group was 14.29 (±2.86) and of unvaccinated group 5.92 (± 2.07) (p < 0.001). Measles vaccine effectiveness by serological method was 64.4% (Table II). The case reference method results marginally lower than the laboratory result were (62% and 64.4%, respectively) (p >0.05). Table II__Distribution of Children According to Their Vaccination Status and Antibody Titers
Figures in parentheses shows percentages.
Vaccine efficacy =
(F.R. among non-immunized – F.R. rate among immunized) / (F.R. among non-immunized)
= (119/171 – 29/117) / (119/171) = 64.4%
where, F.R. is the failure rate in the respective group.
Vaccination records were available in 51.4% (n = 108) of the vaccinated group and 47.6% (n = 100) of the unvaccinated group. Based on confirmed records, the attack rate for measles was found to be 11.1% and 32.0% in the vaccinated and unvaccinated groups respectively. Amongst those with records, 18.3% of the vaccinated and 58.6% of the unvaccinated had measles antibody titre <1:8. In those with vaccination records, the vaccine efficacy by the case reference method was 65.3% and by serological method was 68.7% (p >0.05) Discussion The risk ratio of 2.6 obtained in the present study is concordant with risk ratio obtained in other trials, which reported that an unvaccinated child was 2-3 times more prone to develop measles as compared to a vaccinated child(8). A similar study conducted in Najafgarh zone of Delhi observed attack rates of 14.7% and 31.3% in the vaccinated and unvaccinated children, respectively(7). The vaccine efficacy in the same study was calculated to be 53.1%. A multi-centric study also reported the vaccine efficacy range from 61.7% to 75.1%(8). In an outbreak in India in six south Indian villages in 1980, it was seen that none of 121 immunized children developed measles but 198 of unimmunized children did. The vaccine efficacy was thus calculated to be 100%(9). It was observed that 73.3% of vaccinated cases developed measles attack before an interval of 6 months of vaccination, thereby indicating a low level of antibody titer against measles infection after the receipt of vaccine. Inability to show protective antibody titer may be due to waning of antibody titer or lack of initial seroconversion. Since seroconversion is rarely documented after vaccination, therefore, it is difficult to distinguish these two types. The lack of initial seroconversion may be due to usage of inactive vaccine at the time study group was vaccinated or due to host factors such as genetic/physiological unresponsive-ness, inappropriate age, malnutrition, inter-current infection, waning immunity levels, etc. It has been realized that most of the laboratory-based trials on vaccine efficacy are carried out under controlled conditions, giving results which are unrealistic in the field conditions. Under field conditions immunization cannot be strictly supervised and many factors affect the subsequent development of protective antibodies. Vaccine efficacy obtained under field conditions, thus realistically assess the protection afforded by the vaccine against the diseases. The case reference technique for the estimation of measles vaccine efficacy is as effective a tool as serology as shown by the above study. It is a rapid method and can be easily carried out in a community. It is recommended that during vaccination coverage, questions regarding attack of measles can be incorporated. This data obtained on a regular basis can be structured to estimate vaccine efficacy and utilized for evaluation of the vaccination program. Contributors: AP designed the study, collected and analyzed the data and drafted the manuscript; she will act as the guarantor. VKG and MM helped in analysis, interpretation and drafting. AC was responsible for the microbiological supervision and co-drafting. Funding: None. Competing interests: None stated.
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