Spontaneous reporting of adverse events following pandemic infl uenza A ( H 1 N 1 ) immunization in a reference center in the S tate of São Paulo , Brazil

Introduction: This paper describes adverse events (AEs) temporally associated to the pandemic infl uenza A (H1N1) vaccine observed in a reference center in São Paulo, Brazil, during a 2010 mass vaccination campaign. Methods: A retrospective study involving persons who sought medical care for AEs following infl uenza vaccination. Data were retrieved from medical records, vaccine AE notifi cation forms, and a computerized system for immunobiological registration. Results: Sixty-six vaccinees sought medical care for AEs after immunization. The most frequent AEs were fever, headache, myalgia, and pain at the injection site. No serious AEs were reported. Conclusions: Few vaccinees spontaneously reported AEs to infl uenza A (H1N1) vaccine at this center.

In 2010, the Brazilian National Immunization Program conducted a large national vaccination campaign against pandemic influenza A (H1N1) that started on March 8 (10 th epidemiological week).Healthcare workers (HCW) involved in the response to the pandemic were the fi rst group to be vaccinated, followed by pregnant women, indigenous populations, individuals with chronic conditions, healthy children aged 6 to <24 months, healthy adults aged 20-29 years, seniors, and fi nally, healthy adults aged 30-39 years 2 .The monovalent vaccine against 2009 pandemic infl uenza A (A/California/7/2009 H1N1) was available throughout the campaign, while the trivalent influenza vaccine (A/ California/7/2009 (H1N1), A/Perth/16/2009 (H3N2), and B/ Brisbane/60/2008) only became available on April 24 for vaccinating seniors.The vaccination campaign was successful.Totally, 88 million people (46% of the Brazilian population) were vaccinated in 20 weeks (from March 8th to August 1st).It was the biggest vaccination campaign ever conducted in Brazil, exceeding the 67 million people vaccinated against rubella in 2008 3, .The Ministry of Health's goal of vaccinating at least 80% of the target population was surpassed for the whole target population and particularly for persons with chronic conditions, children under 2 years, adults aged 20 to 29 years, HCW, and indigenous populations 3, .Nationwide, in 2010, there were 773 confi rmed cases of 2,009 pandemic infl uenza A (H1N1) and 99 deaths, which occurred in epidemiological weeks 1 to 35 (from January 3 rd to September 4th, 2010).The peak incidence occurred in epidemiological week 10 (March 7-13, 2010), concomitant with the onset of the vaccination campaign, after which there was a continuous reduction in new cases 4 .
At the Hospital das Clínicas (HC), a large teaching hospital attached to the Faculdade de Medicina da Universidade de São Paulo (FMUSP), the vaccine was available in the Immunization Center (Centro de Referência de Imunobiológicos Especiais, CRIE-HC-FMUSP) throughout the season.In the hospital's main building (Instituto Central), during the vaccination campaign, the vaccine was also available for HCW in readily accessible places during working hours through mobile teams, as has been done since 2006 5 .In this center, 37,497 persons were vaccinated against pandemic influenza A (H1N1) in 2010, including 22,333 HCW and 13,217 individuals with chronic conditions.These numbers far exceeded the numbers of vaccinees in previous seasons.In 2008, 15,689 persons, of whom 7,733 were HCW, were vaccinated in this center and 18,081 persons (8,116 HCW)  Monitoring the safety of vaccines is an important aspect of a vaccination program.A passive surveillance system for adverse events following immunization (AEFI) has been in place in Brazil since the 1990s, and since 2005, reporting any  AEFI is mandatory.In the CRIE-HC-FMUSP, all vaccinees were informed about possible adverse events (AEs) following infl uenza vaccination and advised to return if an AEFI occurred.
The aim of this study was to describe the AEs temporally associated with the pandemic infl uenza A (H1N1) vaccine that were spontaneously reported by vaccinees at the CRIE-HC-FMUSP during the 2010 infl uenza vaccination campaign.
This is a descriptive retrospective study.All persons who sought medical care at the CRIE-HC-FMUSP reporting any AE temporally associated with the infl uenza vaccination during the 2010 season were included in the analysis.The data were collected from the medical records, AEFI notifi cation forms, and the computerized system for immunobiological registration.Variables such as age, sex, reason for vaccine recommendation, the type of vaccine received (monovalent or trivalent), time between vaccination and the fi rst symptoms, reported symptoms and signs, and whether the person had simultaneously received other vaccines were analyzed.
The study was approved by the Research Ethics Committee of the Hospital das Clínicas da FMUSP (protocol n° 0673/10).
During the 2010 season, 66 persons sought medical care at the CRIE-HC-FMUSP due to AEs temporally associated with the vaccination against infl uenza.Their ages ranged from 8 to 68 years; only 1 of the 66 individuals was a child.Most were women (87.9%) and HCW (80.3%) and had received the monovalent vaccine without adjuvant (73.4%).Only 1 person had received the trivalent infl uenza vaccine.The average period of time between vaccination and the onset of symptoms was 48h, and the median was 24h.The longest time between vaccination and the symptoms was 51 days (Table 1).
Systemic AEs following influenza A immunization were reported by 55 (83.3%) vaccinees, most frequently fever, headache, and myalgia (Figure 1).Other less frequent symptoms (reported only once each) were chills, anxiety, bitter mouth, pain and cramps in the lower limbs, eyelid swelling, skin thickening, skin lesion (poorly described in the medical record), painful cervical lymph node, nasal obstruction, red eyes, and Raynaud's phenomenon in a person who had previously presented this symptom.
Eighteen (27.2%) persons reported an AE at the injection site, most frequently, local pain.Other local symptoms, reported only once each, were injection site hematoma and vesicles around the injection site that suggested herpes zoster.Six (9%) persons reported hypersensitivity reactions (Figure 1).
Three persons had received another vaccine simultaneously with the infl uenza vaccine: tetanus and diphtheria toxoids (1), yellow fever vaccine (1), and Measles-Mumps-Rubella vaccine (1).The person who had received both infl uenza and yellow fever vaccines presented with fever, headache, myalgia, and cramps in the lower limbs beginning 2 days after vaccination.Although fever, headache, and myalgia may occur after yellow fever vaccination, this vaccinee associated her symptoms with the infl uenza vaccine.
Most of the AEs temporally associated to the vaccination against pandemic Infl uenza A (H1N1) were reported at the beginning of the immunization campaign: 62.1% of all medical visits occurred in the fi rst 2 weeks of the campaign and 87.8%, in the fi rst 5 weeks (Figure 2).
From January 2 to October 31, 2010, the CRIE-HC-FMUSP team administered 36,008 doses of immunobiologicals other than infl uenza vaccine, which resulted in 15 medical visits due to AEs temporally associated with those immunobiologicals.
At the CRIE-HC-FMUSP, the pandemic infl uenza A (H1N1) vaccine was well tolerated with few vaccinees spontaneously reporting systemic or local AEs.
Healthcare workers and seniors were the majority of the target population served by the CRIE-HC-FMUSP for the infl uenza immunization, which should explain the median age of 55 years of the persons who sought medical care for AEs temporally associated with the pandemic infl uenza vaccination.Additionally, HCW working in the Hospital das Clínicas have easy access to the CRIE-HC-FMUSP, and the fi nding that most

Number of medical visits
persons who sought care due to AEs were women may have been partly due to the gender distribution of HCW at the hospital 6 and possibly due to the general tendency of women to access healthcare services more often than men 7 .
Systemic AEs were more frequent than local AEs, which is similar to what has been observed in other studies [8][9][10] .Systemic AEs that were diffi cult to measure, such as headache, myalgia, and unmeasured fever, were reported most frequently.AEs that were diffi cult to measure, such as pain, also predominated at the injection site.No serious AE was reported.The frequency and severity of the AEs observed in this study were similar to those reported following the seasonal infl uenza vaccine in previous seasons, led by pain and tenderness at the injection site and followed by systemic AEs such as headache, malaise, and myalgia in the fi rst 4 days after immunization 11 .
Our fi ndings are similar to those of a study conducted in Australia, in which a vaccine similar to the one used in the Brazilian mass vaccination campaign (inactivated monovalent infl uenza A (H1N1) vaccine, without adjuvant, with 15 mcg of hemagglutinin and thimerosal) was used.The main AEs observed in the Australian study were pain and tenderness at the injection site, with systemic AEs including headache, malaise, and myalgia 12 .Other studies conducted in Denmark, Italy, China, and Germany in order to evaluate different vaccines with or without adjuvant supported the safety of the 2009 pandemic infl uenza A (H1N1) vaccine.Most of AEs observed in those studies were mild [8][9][10]13 . It hould be pointed out that fever after infl uenza A (H1N1) immunization was more frequently observed in this study (42%) than in those of others 9,13 , possibly because in this study, any report of fever, even if unmeasured, was recorded.Fever and febrile seizures were reported in children under 5 following immunization with an inactivated infl uenza vaccine without adjuvant or thimerosal (Fluvax) in Australia, which led to discontinuation of the use of all 2010 seasonal infl uenza vaccines in healthy children under 5 in Australia 14 .In China, 89.6 million people were vaccinated with a different infl uenza A (H1N1) split virion vaccine, without adjuvant, that was produced domestically.Fever was the most frequent AE reported to the passive AEFI surveillance database (39.1 cases/1 million doses administered) 10 , and most AEs were recorded at the beginning of the vaccination campaign, particularly in the fi rst 5 weeks 10 .
Greater frequency of medical visits due to AEs at the beginning of the vaccination campaign, as well as a greater number of AEs temporally associated with the pandemic infl uenza A (H1N1) vaccination when compared with other immunobiologicals, was expected.There was huge publicity for the pandemic infl uenza A (H1N1) vaccine, which raised awareness for perception and reporting of AEFI.Although the pandemic infl uenza vaccines had the same manufacturing and approval processes used for seasonal infl uenza vaccines and thus were expected to present the same safety profi le as the seasonal vaccines 15 , people saw them as new vaccines.Vaccine safety is a great concern in any mass vaccination campaign, during which huge numbers of persons are immunized in a short period of time, and this might uncover more AEs associated with the vaccine, even if rare.Furthermore, HCWs had been encouraged to report any AE following the infl uenza vaccine 15 .We believe vaccination is the most effective way to prevent infl uenza.Public confi dence in a vaccination program is a key factor for a successful program.Answers to public concerns regarding vaccine safety must be provided to help secure adherence of the target population to the program and achieve high vaccination coverage.Surveillance of vaccine safety when a vaccine is used for routine immunization of specifi c populations is critical.Although limited, passive surveillance of AEFI allows detection of unrecognized AEs, detection of vaccine lots associated with unusual numbers and types of AEs, and monitoring of safety of newly licensed vaccines 15 .

Oliveira
DS et al -Adverse events following pandemic infl uenza A (H1N1) vaccine

FIGURE 2 -
FIGURE 2 -Distribution of medical visits for adverse events following pandemic infl uenza A (H1N1) immunization.

TABLE 1 -
Demographic characteristics, type of vaccine received, and time between vaccination and fi rst symptoms for 66 persons who spontaneously sought medical care due to adverse events following pandemic infl uenza A (H1N1) immunization in a reference center in São Paulo, Brazil, 2010.