key: cord-0967246-g542el9s authors: Tebaa, Amina; Benkirane, Raja; Alj, Loubna; Cherkaoui, Imad; Soulaymani-Bencheikh, Rachida title: Monitoring the safety of influenza A/H1N1 pandemic and seasonal vaccines in Morocco date: 2022-03-29 journal: Ther Adv Vaccines Immunother DOI: 10.1177/25151355221088157 sha: 832ee184bd6781d0a662ec7f364debc7c7a0448f doc_id: 967246 cord_uid: g542el9s BACKGROUND: A vaccination campaign against pandemic influenza A/H1N1 was implemented in Morocco between November 2009 and April 2010. Overall, 705,883 subjects were vaccinated by Pandemrix, Arepanrix, and Panenza. The adverse events following immunization (AEFIs) data comparison was made with the 2014/2015 seasonal influenza vaccination campaign that was specifically investigated. AIM: To evaluate the safety of the 2009 pandemic influenza A/H1N1 vaccine and to compare it to that of 2014 seasonal influenza vaccine. METHODS: During the pandemic vaccination campaign, the Morocco Pharmacovigilance Centre reinforced passive AEFI surveillance with an active and prospective monitoring programme of 1000 immunized people over 6 months at 10 randomly selected vaccination centres. For the 2014/2015 seasonal vaccination campaign, AEFI data were collected from spontaneous notifications. RESULTS: Active monitoring of 2009 pandemic collected 771 AEFI reports, corresponding to an AEFI incidence rate of 77.1% with vaccination by either Pandemrix or Arepanrix vaccine in 95% of cases. Reported AEFI were most frequently local (37.7%), general (29.5%), and neurological reactions (20.3%). Most of the AEFI (95.5%) were observed during the first 48 hours after vaccination, and the remainder within 2 weeks. None of the reported AEFI were serious case. The highest rate of notification was documented for health professionals, followed by patients with diabetes or chronic respiratory diseases. Concerning passive surveillance, the AEFI notification rate was significantly higher for the 2009/2010 pandemic vaccine (3.1 vs 1.2 per 10,000). However, there was no significant difference between pandemic and seasonal vaccination with regards to the serious adverse events (SAE) notification rate (0.3 vs 0.2 per 10,000). CONCLUSION: Data analysis indicates that the vaccines used against 2009 pandemic influenza in Morocco have a satisfactory safety profile, similar to the seasonal influenza vaccine with the exception of local reactions as observed previously in other countries. The World Health Organization (WHO) declared in June 2009 that the novel influenza strain A/ H1N1 had met criteria for an influenza pandemic, 1 the first declared for four decades. 2 The emergence of this strain stimulated the development of specific vaccines in 2009 and prompted national and international health authorities to implement guidelines in order to limit transmission and mortality. At this time, the available safety data of vaccines were derived from clinical trials, which collected data on the most common adverse events (AEs) to be expected from each vaccine. However, it is essential to complete these trials with post-marketing surveillance studies in larger populations followed for longer periods of time. Such studies are designed to collect and analyse reports of rare and late adverse events following immunization (AEFIs). An AEFI is defined as 'any untoward medical occurrence which follows immunisation but which does not necessarily have a causal relationship with the usage of the vaccine. 3 The adverse event may be any unfavourable or unexpected sign, abnormal laboratory finding, symptom or disease'. 3 Following the international alert on the influenza pandemic in 2009 and like most other countries, Morocco followed the recommendations and guidelines set out by the WHO and set up vaccination programmes against influenza virus for 'atrisk' populations, such as health professionals, people with chronic diseases or pregnant women. More specifically, the Moroccan vaccination programme recommends the use of two inactivated adjuvanted vaccines (Pandemrix TM and Arepanrix TM from GlaxoSmithKline Biologicals s.a.) and one inactivated non-adjuvanted vaccine (Panenza TM from Sanofi-Pasteur). These pandemic influenza vaccines were made available free of charge to 'at-risk' groups based on the following priorities: pilgrimage to Mecca, health professionals in direct contact with patients in emergency departments or intensive care units, adults with chronic diseases (diabetes, chronic respiratory diseases. and other chronic diseases), pregnant women, babies aged from 6 to 23 months and all individuals who wanted to be vaccinated among the general population. On the basis of vaccine producers and WHO recommendations and according to the Morocco Ministry of Health instructions (Ministerial Circular No. 190 DELM/36/DP/13 dated 7 December 2009), one dose (0.5 mL) and half a dose (0.25 mL) of vaccine were offered via the intramuscular route to respectively adults whatever their risk group and children aged from 6 to 23 months. Children did not receive a second dose of vaccine due to delayed vaccine delivery and logistical issues. The Centre Anti Poison et de Pharmacovigilance du Maroc (CAPM) developed a reinforced surveillance protocol in order to evaluate the safety of the vaccines used during the 2009 vaccination campaign. This was based on a spontaneous reporting system and on an active case-finding approach using intensive monitoring to follow-up people who had been vaccinated. After the 2009 influenza pandemic, patient concerns about the safety of influenza vaccines continue to be a barrier to vaccine uptake despite the WHO statement that side effects of pandemic influenza A/H1N1 2009 vaccine are similar to those observed with seasonal influenza vaccine. To date, no comparative review of reports of AEs following pandemic influenza A/ H1N1 2009 and seasonal influenza vaccinations in the Moroccan population has been published. In November 2014, Morocco received a donation of 123,310 doses of Southern hemisphere formulation (same formulation as Northern hemisphere 2014-15) Green Cross TM trivalent inactivated and unadjuvanted influenza vaccine from the Partnership for Influenza Vaccine Introduction (PIVI) and Task Force for Global Health (TFGH) through a cooperative agreement on influenza vaccination between the US Centres for Disease Control and Prevention (US CDC) and the Morocco Ministry of Health. This donation allowed the Ministry of Health to expand their current target populations for seasonal influenza vaccine (health care professionals and health professions students) to include diabetics and elderly institutionalized persons. The vaccine campaign was completed by early January 2015 and 62.5% of doses were successfully administered to target populations. Monitoring for AEFIs was done by CAPM based on both routine basis and active monitoring. The objectives of this study were to document the safety of the influenza A/H1N1 vaccines used in 2009 in Morocco and to compare the notification rate of AEs following pandemic influenza vaccination with that of seasonal influenza vaccination. These two studies were conducted in different sites according to the context of vaccination: For pandemic influenza vaccination campaign (2009/2010 ). Ten randomly selected centres were considered. Each centre represented one region of the country and was invited to enrol 100 subjects vaccinated against pandemic influenza. The population eligible for vaccination corresponded to a predefined 'at-risk' population, which included health professionals, patient with diabetes, with chronic respiratory diseases, or other chronic diseases, pregnant women (second quarter to third quarter), babies aged from 6 to 23 months old and others. In addition, we decided to include vaccinated healthy subjects in order to complete the target sample of 100 subjects in the centre. A total sample of 1000 vaccinated subjects was targeted and constituted the national cohort involved in the study. Oral informed consent was obtained from all participating subjects. Each vaccinated subject was followed up closely during the following 6 months, except for pregnant women who were followed-up until the delivery. For seasonal influenza vaccination campaign (2014/2015) . Vaccination was performed using the Southern hemisphere formulation (same formulation as Northern hemisphere 2014-15) Green Cross trivalent inactivated and unadjuvanted influenza vaccine. The CAPM was actively engaged in planning and monitoring the 2014/2015 vaccine campaign. A circular was disseminated to all 83 provinces instructing them to strengthen the existing passive AEFI surveillance system. Any AEFI was spontaneously recorded by local health personal and thereafter reported to provincial, regional, and central levels during or after the campaign according to routine pharmacovigilance monitoring processes in force. For pandemic influenza vaccination campaign (2009/2010) . During the study period (from 1 November 2009 to 16 April 2010), two sources of information were used to monitor the safety of administered vaccines, namely spontaneous notification and active surveillance. Spontaneous notification. Spontaneous notifications considered in this study were reported only by health professionals following their own experience of AEFI or following a declaration of their patients or vaccinated subjects. Spontaneous notification of AEFIs declared by health professionals were documented as part of routine pharmacovigilance monitoring. Health professionals have no legal obligation to report AEFIs spontaneously. However, a national programme was implemented in order to raise awareness of health professionals about the AEFI and in order to encourage them to notify each AEFI spontaneously. Caution is required when interpreting the AEFI data provided by spontaneous notification. Like all passive surveillance data, AEFI data are subject to under-reporting. The AEFI notification rates cannot be interpreted as true incidence rates. Active surveillance. Active surveillance was limited to the national cohort of 1000 'at-risk' subjects. Investigators from the CAPM contacted immunized subjects by telephone at specific times 48 hours, 21 days, and 6 months after immuni-zation and invited to specify any potential AEFI. The self-assessment questionnaire collected data on gender, date of birth, vaccine name, date of vaccination, batch number, the manufacturer of the vaccine and the notification of AEs with the date of onset and resolution. Each individual questionnaire corresponds to one or many notifications included one or many AEs. All AEFIs were notified and reported to the CAPM who classified them according to the Preferred Term (PT) and System Organ Class (SOC) in the WHO Adverse Reaction Terminology 4 and entered them into a specific study register. The AEFIs were considered serious if they resulted in death, required hospitalization or prolonged the hospitalization, were life-threatening, resulted in persistent disability, congenital anomalies or birth defects, or other medically important condition. The relationship between immunization and the appearance of any serious adverse events (SAEs) was assessed by the pharmacovigilance centre. Active surveillance and ad hoc studies (Global Manual on surveillance of AEFIs. WHO, 2014, https://www.who. int/vaccine_safety/publications/Global_Manual_ on_Surveillance_of_AEFI.pdf) are usually conducted in order to further expand passive AEFIs surveillance activities and provide true incidence rates estimation. For seasonal influenza vaccination campaign (2014/2015). All vaccination sites (health units, NGOs, institutional living facilities) used existing (or were provided by) registers to spontaneously record any AEs following the influenza campaign. Each vaccine recipient was also to receive a vaccine card after vaccination. Reports were taken using the standard triplicate pharmacovigilance form deployed throughout all Moroccan health care facilities and reported to the provincial and regional levels. A central team contacted by telephone focal points at provincial and regional levels to activate the AEFIs notification process. The presentation of the results is principally descriptive. Most of the results are presented as frequency counts and percentages, with their 95% confidence intervals in term of AEFI (spontaneous) notification rate for passive surveillance and AEFI (true) incidence for active surveillance. A chi-square test was performed in order to compare frequency distributions when appropriate. For pandemic influenza vaccination campaign (2009/2010) . During the Moroccan vaccination campaign of 2009, 705,883 subjects were vaccinated around the country. Of those, 525,049 received an adjuvanted vaccine, corresponding to 74.4% of all subjects. These subjects provided the source population for spontaneous AE reporting. With respect to the national pharmacovigiliance survey, a total of 1000 subjects were enrolled. All potential AEs possibly related to immunization with adjuvanted vaccine (Pandemrix and Arepanrix) and non-adjuvanted vaccine (Panenza) were documented. The largest 'at-risk' groups represented in the survey were health professionals and individuals with diabetes accounting for respectively 400 and 449 subjects, both corresponding to 84.9% of 1000 sujects. On another side, subjects with other chronic diseases, healthy subjects, pregnant women, and children from 6 to 23 months accounted for 77, 68, 67, and 20 subjects, respectively, corresponding together to only 23.2% of 1000 sujects. Males predominated among health professionals (63.2%) and healthy subjects (57.4 %), whereas females predominated among individuals with diabetes (52.8 %) or with other chronic diseases (54.5 %) and children from 6 to 23 months (60.0%; Table 1 ). The median age of the study participants was 40.25 years (10 months-80 years). The majority of subjects (n = 908; 90.8%) received one dose of an adjuvanted vaccine (n = 549; 54.9% for Arepanrix and n = 359; 35.9% for Pandemrix) and the rest (n = 92; 9.2%) received one dose of a non-adjuvanted vaccine (Panenza). In these provinces, 104,023 persons were to be vaccinated in the selected target population. These provinces indicated they received 110,092 doses of Green Cross trivalent inactivated influenza vaccine and of these, 65,018 (62.5%) were successfully administered. Vaccine uptake was journals.sagepub.com/home/tav 5 highest among diabetics among whom 37,761 (68.2%) were vaccinated, followed by health professionals with 17,186 (54.8%) vaccinated. Uptake among health students varied by type of institution due to the coincidence with the school examinations period with 564 (5.2%) vaccinations for students in medical and dental faculties and 4307 (60.5%) vaccinations for those in nurse institutes. Finally, uptake among elderly was extremely high with 5200 vaccinations (98.1%), most likely reflecting easier logistic issues of vaccine delivery to a residential population. Redeployment numbers represent influenza vaccine originally designated for one target population that was redirected to another facility or target population in the province. Overall, 12.3% of vaccine was redeployed to maximize the use of vaccine, although these data were not consistently recorded by all provinces. Among the source population of 705,883 subjects vaccinated, a total of 222 individuals spontaneously notified AEFIs during the study period. This corresponds to a (spontaneous) notification rate of 3.1 per 10,000 immunized subjects in the country (95% CI: 2.7-3.6 per 10,000; Table 2 ). The highest spontaneous notification rate was recorded from health professionals themselves (39.5 per 10,000 immunized subjects) followed by those declared, via health professionals, by healthy subjects and subjects with diabetes or respiratory diseases). In this group, data on demographics were available for 126 subjects, of whom 84 (66.7%) were women and 121 (96.0%) were adults. Active surveillance cohort. Among the thousand subjects involved in the national intensive pharmacovigilance survey, 771 reported experiencing AEFIs corresponding to a (true) incidence of 77.1% of the immunized population involved in this survey (95% CI: 74.5-79.7 %). Data on demographics of this population were available for 746 subjects, of whom 336 (41.7%) were women, 738 (99.0%) were adults (of whom 20 were aged > 65 years) and eight (1.0%) were children (data were missing for 27 subjects). Table 2 ). During the national intensive pharmacovigilance survey, the immunized subjects were followed-up during three reference periods: 48 hours, 21 days, and 6 months after immunization. The majority (n = 803; 82.5%) of AEs were reported during the first follow-up period (48 hours after immunization) and the rest (n = 170; 17.5%) were reported during the second follow-up period (21 days following immunization). No AEs were reported during the last follow-up (6 months after immunization). No SAEs were reported in the national intensive pharmacovigilance survey. From spontaneous reporting, 21 (9.5%) subjects reported an event classified as an SAE. These involved nine patients (42.8%) who were hospitalized, for All these cases were reported in subjects with diabetes (15 cases) or chronic respiratory diseases (6 cases). The causal relationship between immunization and SAEs was assessed and considered absent in 8 (38.1%) cases, possible in 11 (52.4%) cases and unlikely in 2 (9.5%) cases (Table 5 ). All serious cases were observed following vaccination with adjuvanted vaccine. Three persons died during the study. No causal relationship between immunization and the deaths was suspected. Two deaths were due to autopsy-confirmed bowel obstruction which occurred concurrently with the vaccination and the third concerned a very old subject suffering from two chronic diseases (diabetes and hypertension). Among the eight AEFI cases, seven were mild and one was a case of Guillain-Barré Syndrome (GBS) and therefore classified as an SAE. An investigation was conducted at the provincial level and the GBS case recovered successfully. The corresponding SAE notification rate was 0.15 per 10,000 doses administered (95% CI: 0.0-0.5 per 10,000). The (spontaneous) notification rate of SAE (0.3 per 10,000; 95% CI: Table 5 ). During the study, two sources of information were used to collect AEFIs. The first procedure consists on a spontaneous reporting of AEFIs, and the second procedure consists on a national active pharmacovigilance survey using a selfassessment questionnaire. A total of 222 spontaneous notifications were recorded during the immunization campaign. This corresponds to 3.2 notifications per 10,000 immunized subjects. This rate was intermediate between those reported in Ireland and United States (0.63 and 0.82, respectively, spontaneous notifications per 10,000 subjects) 6, 7 and those reported in France and Denmark (9.4 and 17.9, respectively, spontaneous notifications per 10,000). 8, 9 However, this (spontaneous) notification rate was significantly higher than that of 1.2 per 10,000 immunized subjects observed for 2014/2015 seasonal vaccine. Both clinical trials and active surveillance studies have shown that pandemic adjuvanted vaccines induce frequent local reactions 10-12 that were up to 30.8% with the spontaneous reporting in our study. During the active pharmacovigilance survey, among the thousand subjects responding to the self-assessment questionnaire, 771 (77.1%) subjects notified AEs. This rate is very high compared to that of passive AEs surveillance. Like all passive surveillance data, AEFI data are subject to under-reporting, Thus the active notification rate observed in Morocco could be interpreted as true AEFI incidence rates but it seemed to be higher compared to the rate reported in Slovenia (29.2%) 10 or in Korea (6.3%) 11 for example. However, it should be noted that the direct comparison of the spontaneous or active notification rates between countries was difficult because many specific factors can influence these rates. It includes for example, the intra-individual specificity (such as age, community, and background conditions) and the reactogenicity of each subject to the type of vaccine used. The background rate of disease (such as multiple sclerosis or autoimmune disease) was an important aspect in the assessment of vaccine safety and should be considered in the determination of the AEFIs. 3 This aspect may help to distinguish between legitimate AEs and events that are associated with but not caused by vaccination. 13 In general, the type of AEFIs observed in our study were comparable to those reported in the clinical trials and the post-marketing vaccine surveillance system as indicated in the summary of product characteristics (SPC) of each used vaccine at the time of study. [14] [15] [16] Based on the SOC, application site disorders such as pain and injection site reaction were reported by over one-third of subjects as evoked above, followed by general disorders such as fever. These results are consistent with several studies using the same or different influenza vaccine where around 50%-60% of subjects reported local site reactions. 10, 12 Moreover, our study results are consistent with the information in the pandemic vaccines package insert. This information as we observed in Morocco ( Table 4 ) is specifying that some local reactions such as pain at injection site or general disorders like fever or headache are expexted to be very common (more than 10%). journals.sagepub.com/home/tav 11 Also, others side effects as redness and swelling at the injection or shivering were found common (1-10%) as expected. However, some important side effects seems to be more commonly found (vertigo and paraesthesia) or less commonly found (fatigue) in our study comparatively to the vaccine package insert information. At last, gastrointestinal system disorders (diarrhoea, vomiting, and abdominal pain) expected to be uncommon (0.1-1%) were more commonly notifyed by spontaneous reporting of AEFIs probably due to the background rate of digestive diseases. In addition, we observed in our study that among the 1222 analysable subjects, only one reported a GBS considering that this event is expected to be very rare (less than 0.01%) according to the vaccines package insert information. Nevertheless, no causal relationship between the occurrence of this SAE and the immunization was detected. In the literature, it was suggested that during a mass immunization with pandemic H1N1 influenza vaccines involving for example 10 millions subjects, it can be predicted that about 22 will develop GBS. 13 Among the 'at-risk population', no new or unexpected events were observed in immunized pregnant women. However, subjects with diabetic reported the majority of SAEs (15/21 subjects). This result suggests that diabetic seems to be the most important risk factor to develop SAEs following immunization against H1N1. It was noted in our study that the notification rate reported during the active pharmacovigilance phase was significantly higher than the rate found in the spontaneous reporting phase (p < 0.0002). This may be explained by under-reporting of passive surveillance as stated above but also by the fact that subjects in the active pharmacovigilance phase were pre-selected and identified as an 'at risk population', and are thus more 'susceptibles' to experience AEs. In addition, these subjects are followed during the study period which gives them the opportunity to report each AEs during the study course. Moreover, the spontaneous notifications may be associated with a loss of certain information. For example, subjects may forget to report a potential AE to their physicians because they do not associated it to the immunization or they believe that it was associated with their own disease. Many proposals are recommended especially by the WHO, to strenghten a rountine and passive AEFI notification system. Stimulated passive AEFI surveillance is a good example of such recommendations that have proven their relevance in the COVID-19 vaccination context. For this purpose, health staff should be trained, sensitized, and followed-up by a central AEFI monitoring centre via a network of focal points at local levels. Once an AEFI is detected, an agreed protocol is used for the patient care and management. In parallel, information and communication technology tools should be promoted to allow a more reactive transmission of reports with daily data review at different administrative levels to generate possible signals for adequate response. This study has some limitations. First, the direct comparison between adjuvanted and non-adjuvanted vaccines was not robust because the background conditions of these two groups were different. Second, it is difficult to stress the causal relationship between the vaccination and the occurrence of AEs based on the information provided in our study. Additional methods such as the comparison of observed and expected AEs from the health databases or studies based on individual-level data on exposure and outcome should be of particular interest. However, the combination of the active pharmacovigilance survey and the spontaneous reporting used in our study seems to be an adequate method to collect AEs in Morocco because the two methods are complementary and allow to build the health database in this country. Other methods were used around the world and were adapted according to local specificity of each country. For example, it was shown in United Kingdom that a real-time surveillance of AEFIs with H1N1 vaccines (based on a web reporting system (Yellow Card Scheme ® ) and on a paper reports) confronted to a mathematical computing events would be expected after immunization should be an optimal strategy for the assessment of vaccine safety. 18 This study is the first report describing the monitoring of the safety of influenza A/H1N1 pandemic vaccine in Morocco and to compare it with that of the 2014/2015 seasonal influenza vaccine This article described the method and the results of the AEs monitoring during the 2009 pandemic which was based on two systems of collection of information; the spontaneous reporting and the active surveillance of AEFIs. This study shows that according to these sources of information, no new AEFIs (serious or not serious) with adjuvanted or non-adjuvanted vaccines were observed in Morocco from November 2009 to April 2010. This indicates that the 2009 pandemic influenza A/H1N1 vaccines used in Morocco seems to have a good safety profile similar to seasonal influenza vaccine with the exception of local reactions. Continuous monitoring of seasonal vaccines is necessary in order to ensure a long-term safety of these vaccines. In addition, other supplementary methods which detect and evaluate rare and late AEFIs should also be considered in the near future. Amina Tebaa: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision Validation; Visualization; Writing -original draft Writing -review & editing Raja Benkirane: Investigation; Resources Validation; Visualization Loubna Alj: Validation; Visualization Imad Cherkaoui: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision Validation; Visualization; Writing -original draft Writing -review & editing Conceptualization; Funding acquisition; Project administration; Resources; Supervision; Validation New influenza A (H1N1) virus: global epidemiological situation A (H1N1) influenza virus pandemic: a review Adverse Events Following Immunization (AEFI) World Health Organization. The WHO Adverse Reaction Terminology Pandemic influenza A (H1N1) 2009 virus vaccine -conclusions and recommendations from the October 2009 meeting of the immunization Strategic Advisory Group of Experts UPDATE on national monitoring experience with pandemic H1N1 vaccines Centers for Disease Control Prevention. Safety of Influenza A (H1N1) 2009 Monovalent Vaccines -United States National campaign of vaccination against the flu A (H1N1) v: national follow-up of pharmacovigilance Spontaneous reporting of adverse events following immunisation against pandemic influenza in Denmark Surveillance of adverse events following immunization against pandemic influenza in Slovenia in season 2009/10 Active surveillance of adverse events following immunization against pandemic influenza A (H1N1) in Korea Monitoring the safety of influenza A (H1N1) vaccine using web-based intensive monitoring Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines Summary of Product Characteristics (SPC) Arepanrix Public assessment report -Scientific Discussion-Panenza-Pandemic influenza vaccine (H1N1) Short and long-term safety of the 2009 AS03-adjuvanted pandemic vaccine H1N1 vaccine safety: real-time surveillance in the UK Visit SAGE journals online journals.sagepub.com/ home/tav The authors wish to acknowledge the investiga- The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The pandemic influenza vaccination campaign study has been funded by the Centre Anti Poison et de Pharmacovigilance du Maroc and the seasonal influenza vaccination campaign was supported by the US Centres for Disease Control and Prevention through its Cooperative Agreement with the Morocco Ministry of Health (grant number IP820). Amina Tebaa https://orcid.org/0000-0002-1976-1075 The findings and conclusion of this paper are those of the authors and do not necessarily represent the official position of the US Centres for Disease Control and Prevention.