Pharmacovigilance during mass immunization campaign with MenAfrivac τm in Cameroon

Background. Immunization is one of the most cost effective public health interventions and is estimated to have greatly reduced diseases, disabilities, deaths, and inequities worldwide. To date, it has allowed totally eradicating one disease and putting more than 7 others under control. After testing in clinical trials, only vaccines that meet the requirements of safety and effectiveness are registered and authorized by competent authorities to be used in routine and mass immunization campaigns. However, it is known that whatever may be the performances, clinical phases of a vaccine cannot detect all related adverse events following immunization (AEFIs). This is supported by the fact that the sample size of clinical trials is insufficient to detect rare AEFIs; a given fraction of AEFIs occurring in the marketed phase of vaccine is related to behavioral and biological particularities of vaccinees as they are not rigorously selected as in clinical trials patients, others are related to program errors such as non-compliance to vaccines storage or administration procedures. Thus, AEFIs may occur following administration of licensed vaccines and constitute a risk of damage on the health of patients or a reason for immunization refusal since vaccine safety gets more public attention than vaccination effectiveness.
To anticipate on potentially damaging effects of AEFIs on the health of vaccinees and the adherence of population to immunization, it has been recommended that each vaccination program develops a vaccine pharmacovigilance system to firstly detect, report, investigate, and respond to AEFI and, secondly share information on AEFIs, needed to update the safety profile of each licensed vaccine. Currently published studies show that for a number of reasons, vaccines pharmacovigilance systems are limited to reach their goals in developing countries such as Cameroon. Consequently, several million doses of vaccines are administered to children and pregnant women in routine EPI (Expanded Program on Immunization) and to many other specific groups in immunization campaigns with little information on vaccines safety generated and made available.
The overall goal and specific objectives: This Ph.D aimed to contribute in securing access to immunization by assessing efficient interventions that can be used to improve the pharmacovigilance of licensed vaccine. Its activities were embedded in the vaccination campaign against meningococcal meningitis A, organized in two health region of Cameroon in 2012, with the newly introduced conjugate meningococcal meningitis A vaccine (MenAfrivacTM). The objectives of this thesis were i) to investigate the safety profile of the vaccine MenAfrivacTM in the mass immunization campaign against meningococcal meningitis organized in Adamaoua and North West Health regions of Cameroon; ii) to assess the effect on AEFI reporting, after the meningitis vaccination campaign with MenAfrivacTM, of sending a weekly standardized SMS to health workers in charge of AEFI surveillance in health facilities or conducting standardized supervision of these personnel using skilled supervisors; and iii) to compare the incidence and distribution of MenAfrivacTMAEFIs reported during clinical trial phases to that reported during immunization campaigns.
Method.Three different study designs were used independently to respond to different specific objectives of this thesis. The first was a descriptive and analytical study based on data collected from AEFIs report forms using a preconceived grid. Passive and stimulated AEFIs surveillance were conducted in health facilities and in vaccination sites over a period of two weeks during the vaccination campaign and six weeks thereafter. Incidence and types of AEFIs were described by time after injection, age group, and health region.The second was an open randomized controlled design with three arms. Health facilities that met the inclusion criteria were randomly assigned to receive: i) a weekly standardized SMS asking them to report all medical events occurring during the intervention period in persons immunized during the campaign, ii) a weekly standardized supervisory visit by trained health district focal points for AEFI detection and reporting processes, or iii) no intervention besides routine training and sensitization of health facility teams during health districts coordination meetings (the control group). The primary outcome was the incidence of AEFIs per 100 health facilities per week reported to the Regional Delegation of Public Health rate from week 5-8 after the immunization campaign. The third was a systematic review conducted to identify all published studies reporting adverse events following MenAfrivac™ administration during clinical trials and immunization campaigns. The incidence rate (IR) of overall, local, systemic, serious and types of reported AEFIs were estimated and compared between clinical trials and immunization campaigns studies using the incidence rate difference (IRd).
Findings.
Safety profile of MenAfrivacTMin immunization campaign
Of 2’093’381 persons vaccinated in Adamaoua and North West health regions in 2012, 1’352 AEFIs were reported. Of these, 228 (16.9%) were excluded because they did not meet inclusion criteria. Among the remaining 1’124 (83.1%), the incidence rate was 53.7 AEFIs/100’000 doses administered/8 weeks. Of 82 serious AEFIs reported, 52 (63.4%) met the case definition. Twenty-three (28.1%) were investigated, of which 4 (17.4%) were probably related to the vaccination (incidence rate: 0.2 AEFIs/100’000 doses administered/8 weeks). Fever was the commonest AEFI with 626 cases (incidence rate: 31.4 AEFIs/100’000 doses administered/8 weeks). Proportions of subjects with different primary SOC (system organ class) disorders varied by age group, gastro-intestinal and respiratory being more frequent in children aged <4 years and neurological and general conditions more in adults for example.
Effects of SMS or supervision on AEFI reporting.
A total of 348 (77.2%) of 451 health facilities were included, and 116 assigned to each of three groups. The incidence rate of reported AEFIs per 100 health facility per week was 20.0 (15.9-24.1) in the SMS group, 40.2 (34.4-46.0) in supervision group and 13.6 (10.1-16.9) in the control group. Supervision led to a significant increase of AEFI reporting rate compared to SMS [adjusted RR=2.1 (1.6-2.7; p<0.001] and control [RR=2.8(2.1-3.7); p<0.001)] groups. The effect of SMS led to some increase in AEFI reporting rate compared to the control group, but the difference was not statistically significant [RR =1.4(0.8-1.6); p=0.07)].
Safety profile of MenAfrivacTM in clinical trials and vaccination campaigns
Seven studies were included from 6 publications including 4 clinical trials and 3 immunization campaigns. The overall AEFI IR was 4.6 (4.5-4.7) per 100’000 doses administered per week. In clinical trials studies, the IR per 100’000 doses administered per week of overall, local, and systemic AEFIs were 10’047, 11’499, and 17’248 respectively. In immunization campaigns, these values for overall, local, and systemic AEFIs were 4.0, 0.59, and 3.12 respectively. None of 10 serious AEFIs reported during clinical trials was related to the vaccine. Of 41 serious AEFIs reported during immunization campaigns, 5 were probably related to vaccine. IR of AEFIs were higher in clinical trials than in immunization campaigns studies, the difference (IRd) for overall AEFIs being of 10043 (95% CI 10042-10044) per 100’000 doses per week, for local of 11’498 (11’498-11’498), for systemic of 17’245 (17’245-17’245)] and for serious AEFIs of 1.55 (1.54-1.56). The AEFI IR decreased by more than 99.9% for overall, local, systemic and 99.5% for serious AEFIs from clinical trials to immunization campaigns.
Conclusion
Neither new safety signal nor increased incidence of serious AEFIs compared to previous mass immunization campaign withMenAfrivacTMwas observed. There were age differences in incidence and type of AEFIs that are probably related to different background incidence of diseases and different susceptibilities or reporting rates in these different age groups.
Supervision was more effective than SMS or routine training in improving AEFI reporting rate. It should be part of any AEFI surveillance system. SMS could be useful in improving AEFI reporting rates but strategies need to be found to improve its effectiveness, and thus maximize its benefits.
The magnitude of the difference between IR of AEFI as evaluated in the controlled setting of clinical trials and more pragmatic approach of mass vaccination campaigns was huge. IR of AEFIs was more than 99% lower in vaccination campaigns than in clinical trials, including for the reporting of serious ones. Although the objective of pharmacovigilance is not to identify all minor AEFIs, sustainable strategies including for example standardization of hospital registries with information on vaccination status to improve active case detection in hospitals to allow better reporting and investigation of causality and stimulation of reporting using adequate supervision and communication technologies such as SMS reminders need to be put in place.