Largest measles epidemic in North America in a decade--Quebec, Canada, 2011: contribution of susceptibility, serendipity, and superspreading events.

BACKGROUND: The largest measles epidemic in North America in the last decade, occurred in 2011 in Quebec, Canada, where rates of 1- and 2-dose vaccine coverage among children 3 years of age were 95%-97% and 90%, respectively, with 3%-5% unvaccinated. METHODS: Case patients identified through passive surveillance and outbreak investigation were contacted to determine clinical course, vaccination status, and possible source of infection. RESULTS: There were 21 measles importations and 725 cases. A superspreading event triggered by 1 importation resulted in sustained transmission and 678 cases. The overall incidence was 9.1 per 100,000; the highest incidence was in adolescents 12-17 years old (75.6 per 100,000), who comprised 56% of case patients. Among adolescents, 22% had received 2 vaccine doses. Outbreak investigation showed this proportion to have been an underestimate; active case finding identified 130% more cases among 2-dose recipients. Two-dose recipients had milder illness and a significantly lower risk of hospitalization than those who were unvaccinated or single-dose recipients. CONCLUSIONS: A chance superspreading event revealed an overall level of immunity barely above the elimination threshold when unexpected vulnerability in 2-dose recipients was taken into account. Unvaccinated individuals remain the immunization priority, but a better understanding of susceptibility in 2-dose recipients is needed to define effective interventions if elimination is to be achieved.

Risk of Guillain-Barré syndrome following H1N1 influenza vaccination in Quebec.

CONTEXT: In fall 2009 in Quebec, Canada, an immunization campaign was launched against the 2009 influenza A(H1N1) pandemic strain, mostly using an AS03 adjuvant vaccine. By the end of the year, 57% of the 7.8 million residents had been vaccinated. OBJECTIVE: To assess the risk of Guillain-Barré syndrome (GBS) following pandemic influenza vaccine administration. DESIGN: Population-based cohort study with follow-up over the 6-month period October 2009 through March 2010. The investigation was ordered by the chief medical officer of health in accordance with the Quebec Public Health Act. SETTING: All acute care hospitals and neurology clinics in Quebec. POPULATION: Suspected and confirmed GBS cases reported by physicians, mostly neurologists, during active surveillance or identified in the provincial hospital summary discharge database. Medical records were reviewed and cases classified according to Brighton Collaboration definitions (categorized as level 1, 2, or 3, corresponding to criteria of decreasing certainty in diagnosis). Immunization status was verified and denominators were estimated from the provincial immunization registry (4.4 million vaccinated) and census data (total target population aged ≥6 months, 7.8 million), with a total of 3,623,046 person-years of observation. MAIN OUTCOME MEASURES: Relative and attributable risks were calculated using a Poisson model and the self-controlled case-series method. RESULTS: Over a 6-month period, 83 confirmed GBS cases were identified, including 71 Brighton level 1 through 3 cases. Twenty-five confirmed cases had been vaccinated against 2009 influenza A(H1N1) 8 or fewer weeks before disease onset, with most (19/25) vaccinated 4 or fewer weeks before onset. In the Poisson model, the age- and sex-adjusted relative risk was 1.80 (95% CI, 1.12-2.87) for all confirmed cases during the 8-week postvaccination period and was 2.75 (95% CI, 1.63-4.62) during the 4-week postvaccination period. Using the self-controlled case-series method, relative risk estimates during the 4-week postvaccination period were 3.02 (95% CI, 1.64-5.56) for all confirmed cases (n = 42) and 2.33 (95% CI, 1.19-4.57) for Brighton level 1 through 3 cases (n = 36). The number of GBS cases attributable to vaccination was approximately 2 per 1 million doses. There was no indication of an excess risk in persons younger than 50 years. CONCLUSIONS: In Quebec, the 2009 influenza A(H1N1) vaccine was associated with a small but significant risk of GBS. It is likely that the benefits of immunization outweigh the risks.

Rate of Recurrence of Adverse Events Following Immunization: Results of 19 Years of Surveillance In Quebec, Canada.

BACKGROUND: While adverse events following immunization (AEFI) are frequent, there are limited data on the safety of reimmunizing patients who had a prior AEFI. Our objective was to estimate the rate and severity of AEFI recurrences. METHODS: We analyzed data from the AEFI passive surveillance system in Quebec, Canada, that collects information on reimmunization of patients who had a prior AEFI. Patients with an initial AEFI reported to the surveillance system between 1998 and 2016 were included. Rate of AEFI recurrence was calculated as number of patients with recurrence/total number of patients reimmunized. RESULTS: Overall, 1350 patients were reimmunized, of which 59% were 2 years of age or younger. The AEFI recurred in 16% (215/1350) of patients, of whom 18% (42/215) rated the recurrence as more severe than the initial AEFI. Large local reactions extending beyond the nearest joint and lasting 4 days or more had the highest recurrence rate (67%, 6/9). Patients with hypotonic hyporesponsive episodes had the lowest rate of recurrence (2%, 1/50). Allergic-like events recurred in 12% (76/659) of patients, but none developed anaphylaxis. Of 33 patients with seizures following measles mumps rubella with/without varicella vaccine, none had a recurrence. Compared with patients with nonserious AEFIs, those with serious AEFIs were less often reimmunized (60% versus 80%; rate ratio: 0.8; 95% confidence interval: 0.66-0.86). CONCLUSIONS: Most patients with a history of mild or moderate AEFI can be safely reimmunized. Additional studies are needed in patients with serious AEFIs who are less likely to be reimmunized.

Nephrotic syndrome following four-component meningococcal B vaccination: Epidemiologic investigation of a surveillance signal.

BACKGROUND: In May 2014, a mass vaccination campaign with four-component meningococcal serogroup B (4CMenB) vaccine was launched in a localized region of Quebec, Canada experiencing high invasive meningococcal B disease endemicity. Active post-marketing surveillance identified several cases of nephrotic syndrome (NS) among ∼49,000 vaccinated individuals aged 2 months to 20 years. We report the epidemiologic investigation of this potential vaccine safety signal. METHODS: Active vaccine safety surveillance was conducted electronically, with participants completing an online questionnaire prompted at 7 days after each dose and 6 months following the last dose. Additional NS cases were sought from provincial hospitalization and emergency room databases. RESULTS: In the year following the first dose of 4CMenB vaccination, four confirmed NS cases (three hospitalized) were identified among vaccinated children 2-5-years-old with onset several months post-vaccination. None had renal biopsy but given their age, and positive response to steroids, idiopathic NS was presumptively diagnosed. Among vaccinated children 1-9-years-old, the NS incidence in the year post-vaccination was 17.7 per 100,000 (1 per 5650 vaccinees) with an NS hospitalization rate (i.e. excluding the outpatient case) that was 3.6-fold higher (95%CI = 0.7-11.8; p = 0.12) than the rest of the province for the same period, and 8.3-fold greater (95%CI = 1.1-62.0; p = 0.039) than during the eight years preceding the immunization campaign in the affected region. CONCLUSION: Active safety surveillance identified an unexpected increase in NS incidence following 4CMenB vaccination. Further epidemiological investigation identified four vaccinated cases in total over a 12 month period of follow up. The greater risk in vaccinees had wide confidence intervals with he lower limit including or just above the nul value, an observation with no or marginal statistical significance. The temporal association with vaccination may be explained by other causes and/or chance clustering of a rare event unrelated to vaccination. To confirm or refute a potential link to vaccination, surveillance in other jurisdictions administering 4CMenB to children 1-9-years-old is needed.

Investigation of an increase in large local reactions following vaccine schedule change to include DTaP-HB-IPV-Hib (Infanrix-hexa®) and MMRV (ProQuad®) at 18 months of age.

CONTEXT: In 2015 in Quebec, Canada, the passive vaccine adverse event reporting system detected an increase in large local reactions associated with vaccines recommended at the 18-month visit. This followed changes to the pediatric vaccine schedule to include hexavalent diphtheria-tetanus-acellular-pertusis-inactivated polio-Haemophilus influenzae type b-hepatitis B vaccine (DTaP-IPV-Hib-HB, Infanrix-hexa®, GSK) and quadrivalent measles-mumps-rubella-varicella vaccine (MMRV, ProQuad®, Merck) as 18-month booster doses. OBJECTIVES: To determine if the excess of large local reactions was caused by a specific vaccine or their co-administration in the same limb or during the same visit. METHODS: A case-control study was conducted among cases born between January 2012 and April 2015 with a large local reaction following MMR ±â€¯V or DTaP-IPV-Hib ±â€¯HB vaccines administered between 16 and 23 months of age. Controls were randomly selected from the provincial medicare database among children born during the same period. RESULTS: Our analysis included 96 cases and 494 controls vaccinated with MMRV or DTaP-IPV-Hib ±â€¯HB vaccines. Among the 96 cases, 46% had a cellulitis and 54% had an injection site reaction extending beyond the nearest joint and/or lasting ≥ 4 days. Among the 39 cases who were immunized in different limbs, 77% of the large local reactions were located at the Infanrix-hexa® site, 5% at the DTaP-IPV-Hib site and 18% at the ProQuad® site. Large local reactions were significantly more frequent with Infanrix-hexa® than with DTaP-IPV-Hib vaccine (OR 5.9 95% CI: 1.4-25.7). Administration of ProQuad® and Infanrix-hexa® in the same limb did not increase the risk of large local reactions. CONCLUSION: This investigation suggested that most large local reactions were causally associated with the Infanrix-hexa® vaccine and that the risk was not greater when ProQuad® and Infanrix-hexa® were administered in the same limb. Given the improved vaccine coverage for hepatitis B, benefit-risk analysis likely still favours ongoing use of Infanrix-hexa® with informed parental consent.

Short-term safety of 4CMenB vaccine during a mass meningococcal B vaccination campaign in Quebec, Canada.

BACKGROUND: To address a high incidence of serogroup B invasive meningococcal disease (IMD-B) in the Saguenay-Lac-Saint-Jean region, Quebec, Canada, a mass vaccination campaign targeting nearly 60,000 individuals ≤20 years old was launched in May 2014. Because of the limited clinical experience with the four-component meningococcal B vaccine (4CMenB), active surveillance for adverse events following immunization (AEFI) was conducted. This paper reports 4CMenB AEFI surveillance findings. METHODS: Active surveillance assessed AEFIs with acute onset within 7-days post-immunization, AEFI-associated absenteeism and medical consultations, impact of antipyretic prophylaxis and coadministration of other vaccines. RESULTS: By July 17, 2015, 83% and 77% of the 59,098 individuals targeted by the campaign had received a first and a second dose of 4CMenB. The incidence of fever on days1-2 was highest in children <2 years old but only 0.6% reported a temperature ≥40◦C. Among children <10 years old, ≥2doses of acetaminophen prophylaxis significantly reduced fever incidence on days1-2 after dose1&2. Absenteeism or a medical consultation during the 7 days following vaccination was reported by 6.2% of vaccinees post-dose1 and 9.2% post-dose2 and was most often reported in association with fever/malaise (4.2%) or injection site reactions (3.6%). CONCLUSION: Large-scale population-based surveillance identified a 7-day reactogenicity profile consistent with earlier clinical trials with the 4CMenB vaccine but indicating frequent AEFI-associated absenteeism and medical consultations affecting the societal cost of this vaccine. We conclude acceptable vaccine safety and risk-benefit profile overall on the short term, particularly as an intervention to address a high regional incidence of IMD-B.

Prevalence of risk factors for acquiring measles during the 2011 outbreak in Quebec and impact of the province-wide school-based vaccination campaign on population immunity.

BACKGROUND: A large measles outbreak occurred in Quebec, Canada, in 2011. Although nearly two-thirds of the cases occurred in only two health districts, a mass vaccination campaign targeting all Quebec elementary and high school students without valid two-dose history was undertaken to prevent future outbreaks. We compared rates of non-vaccination and age at first measles vaccine dose among students in the two most-affected districts and the rest of the province and estimated the improvement in overall student measles immunity due to the mass school-based vaccination campaign. METHODS: Data were extracted from the provincial vaccination registry for students in kindergarten to grade 11 during the 2011/2012 school year. A telephone survey was conducted in three sub-groups: students whose first measles vaccine dose recorded in the vaccination registry was received during the 2011 school vaccination campaign; students with no dose recorded in the registry whose parents refused receipt during the school campaign; and students with no dose recorded in the registry and no information about parental consent/refusal during the school campaign. RESULTS: Neither the prevalence of being non-vaccinated nor a younger age at first pediatric dose were higher in the two most-affected districts versus the rest of the province. The school campaign vaccinated nearly 8% of all students including 7% who previously received at least one dose. Before the outbreak, 3% of students were not vaccinated and one-third of these (1%/3%) were vaccinated during the campaign. The campaign likely increased the absolute school population immunity by just 1.7%. CONCLUSION: The concentration of measles cases in the two most-affected health districts during the large Quebec outbreak is not explained by more students who were unvaccinated or who had received their first vaccine dose at a younger age. The vaccination campaign reached one-third of unvaccinated students and only marginally improved population immunity.

Paresthesia and sensory disturbances associated with 2009 pandemic vaccine receipt: Clinical features and risk factors.

BACKGROUND: Paresthesia was the third-most-common adverse event following immunization (AEFI) with 2009 monovalent AS03-adjuvanted A(H1N1)pdm09 vaccine in Quebec, Canada and was also frequently reported in Europe. This study assessed clinical features and risk factors associated with this unexpected AEFI. METHODS: Reports to the passive surveillance system were summarized. A case-control study was conducted to assess risk factors and additional investigations were undertaken among cases with symptoms persisting ≥12 months. RESULTS: There were 328 reports of paresthesia affecting the vaccinated arm (58%), but also face (45%), lower limbs (40%) and back/thorax (23%) with numbness but also muscle weakness (61%), motor impairment (61%), generalized myalgia (37%), visual (14%) and/or speech effects (15%). Reporting rate was highest in women of reproductive age, peaking at 30-39 years-old (28/100,000 doses administered) and exceeding that of men of the same age (7/100,000 doses) by 4-fold. Median time to onset was 2h. Symptoms subsided within one week in 37% but lasted ≥6 months in 26%. No consistent or objective neurological findings were identified. Risk was increased with allergy history, respiratory illness the day of vaccination, depressive symptoms and family history of pulmonary disease, but decreased with physical activity the day of vaccination, and regular weekly alcohol consumption. CONCLUSION: Paresthesia following 2009 pandemic vaccine receipt lasted several weeks and included other motor-sensory disturbances in an important subset of patients. Although it does not correspond with known neurological disease, and causality remains uncertain, further investigation is warranted to understand the nature and frequency of paresthesia as a possible AEFI with influenza vaccines.

Risk factors associated with anaphylaxis and other allergic-like events following receipt of 2009 monovalent AS03-adjuvanted pandemic influenza vaccine in Quebec, Canada.

INTRODUCTION: In Quebec, Canada, receipt of the 2009 AS03-adjuvanted pandemic H1N1 vaccine was associated with increased risk of anaphylaxis and other allergic-like events (ALE), especially among women of childbearing age. In response to this safety signal, a case-control study was conducted to identify potential risk factors. METHODS: A total of 435 ALE (50 anaphylaxis) occurring <24h following pandemic vaccination were compared to 849 age-gender matched controls randomly selected from the provincial Pandemic Influenza Vaccination Registry. More than 60 potential risk factors were evaluated through phone interviews and included demographic information, medical history, medication use or acute respiratory illnesses (ARI) concurrent with vaccination and other risk factors associated with general allergy. Odds ratios (ORs) with 95% confidence intervals were estimated with unconditional logistic regression. RESULTS: Factors associated with increased risk of anaphylaxis included concurrent ARI (18% cases vs. 4% controls, ORadj 7.67, 95%CI: 3.04-13.37), food allergy (26% cases vs. 4% controls, ORadj 3.84, 95%CI: 1.51-9.74) and vaccination during the first four weeks of the campaign (66% cases vs. 50% controls, ORadj 2.16, 95%CI: 1.10-4.25) whereas alcohol exposure (≥1 drink/week) was associated with reduced risk (29% cases vs. 42% controls, ORadj 0.26, 95%CI: 0.13-0.57). These factors were also significantly associated with any ALE but the strength of association was weaker. Allergy to components found in the vaccine (e.g., egg, thimerosal) was infrequent and did not significantly differ between cases and controls. CONCLUSION: Increased anaphylaxis and other allergic-like events observed in association with AS03-adjuvanted pandemic H1N1 vaccine remain mostly unexplained despite extensive risk factor review. However, prior to mass vaccination with similar formulations this safety signal warrants further consideration and better understanding. In particular, the predominance among women of childbearing age may be a clue to underlying biological or hormonal influences on adverse immunological responses to vaccine.

Increased risk of anaphylaxis following administration of 2009 AS03-adjuvanted monovalent pandemic A/H1N1 (H1N1pdm09) vaccine.

BACKGROUND: Anaphylaxis after trivalent influenza vaccination is typically reported at a rate of <1 per million doses. In Quebec, Canada, anaphylaxis following administration of the monovalent AS03-adjuvanted H1N1pdm09 vaccine was reported through passive surveillance at a rate of 8 per million doses administered. This was 20 times higher than the reporting rate for non-adjuvanted trivalent vaccines administered during the six previous seasons. However, adequate estimation of the incidence of anaphylaxis is hindered by wide variations in definitions and diagnosis. METHODS: Using the Brighton collaboration case definition of anaphylaxis, all cases with allergic symptoms (AS) reported to public health were reviewed to estimate the incidence of anaphylaxis following AS03-adjuvanted H1N1pdm09 vaccine. RESULTS: Among 752 reports of allergic symptoms, 33 were initially reported as anaphylaxis of which 20/33 (60%) met the Brighton definition (19/20 with certainty levels 1 or 2). A total of 38 additional cases with onset within 1h of vaccination also met the Brighton definition of anaphylaxis (27 (71%) with certainty levels 1 or 2). The 58 cases meeting Brighton Level 1 or 2 criteria for anaphylaxis represent a 75% increase over the 33 passively reported and an incidence of 13 per million doses administered. CONCLUSION: A substantial number of patients with early-onset allergic symptoms met the most specific levels of the Brighton case definition but were not reported as anaphylaxis. Based on this specific case definition, the incidence of anaphylaxis after AS03-adjuvanted H1N1pdm09 vaccine substantially exceeded that reported with seasonal influenza vaccines, a signal that warrants better understanding.

Oculo-respiratory syndrome after influenza vaccination: trends over four influenza seasons.

BACKGROUND: Oculo-respiratory syndrome (ORS) following influenza vaccination was identified in Canada in 2000. This report describes trends of ORS reported during four consecutive seasons 2000, 2001, 2002 and 2003 in the province of Quebec, Canada. METHODS: Data come from the vaccine-associated adverse event (VAAE) passive reporting system of the Province of Quebec. RESULTS: The rate of ORS reported per 100000 doses distributed declined from 46.6 in 2000 to 34.2, 20.6 and 9 in 2001, 2002 and 2003, respectively. There was no significant difference in rates for ORS between the two vaccines in use in Canada (Fluviral and Vaxigrip) both in 2001 and 2002. During the 4 years, incidence was highest in people aged 40-59 years and declined in older age groups. The clinical profile of ORS has remained remarkably stable over years. Overall, ocular, respiratory symptoms or facial edema were reported by 58%, 84% and 31% of patients, respectively, and 15% had symptoms including all three symptom categories. ORS lasted more than a week in 8-13% of the cases. CONCLUSION: ORS is an adverse event that occurred with both influenza vaccines used in Canada. Its frequency has declined substantially but is still present after 4 years. It constitutes a clinical entity distinct from anaphylactic allergy. Unlike anaphylaxis, ORS does not constitute an absolute contraindication to further doses.

The clinical spectrum of the oculo-respiratory syndrome after influenza vaccination.

Oculo-respiratory syndrome (ORS), a new influenza vaccine associated adverse event, was identified in 2000. The 2000 case definition (ORS-2000) required the presence of bilateral red eyes or respiratory symptoms or facial edema occurring between 2 and 24h following immunization and lasting 24 h), ORS-persistors (duration >48 h).Overall, the distribution of symptoms was similar between ORS-2000 and other case categories. ORS-early and ORS-late had less ocular involvement, ORS-late and ORS-persistors had more cough and sore throat, ORS-early had more facial edema and ORS-late had less. In comparison to ORS-2000, ORS-early were younger whereas ORS-persistors and ORS-late were significantly older suggesting that clinical manifestations of ORS vary with age with a more rapid induction of symptoms in younger individuals and longer duration for older ones.

Oculo-respiratory syndrome following influenza vaccination: evidence for occurrence with more than one influenza vaccine.

We assessed the occurrence of oculo-respiratory syndrome (ORS) following two influenza vaccines: Fluviral (Shire Biologics) or Vaxigrip (Aventis Pasteur). ORS was identified amongst 5.3 and 4.6% of recipients, respectively (P=0.54). With both vaccines, the risk of ORS was much greater in individuals who had ORS the previous year (2000) than in those without such history. In multivariate analysis, the odds ratio for ORS for patients with a prior history of ORS varied between 9.4 and 9.6 (P<0.001) whereas that comparing Fluviral and Vaxigrip varied between 1.5 and 1.9 (P=0.02-0.05). ORS is an adverse event that is present with more than one vaccine and may be present with any influenza vaccines to a greater or lesser degree.