Immunogenicity of 2 and 3 Doses of the Quadrivalent Human Papillomavirus Vaccine up to 120 Months Postvaccination: Follow-up of a Randomized Clinical Trial.

BACKGROUND: Several countries have implemented a 2-dose (2D) human papillomavirus (HPV) vaccination schedule for adolescents based on immunobridging studies. We compared immunogenicity of 2D vs 3-dose (3D) schedules of the quadrivalent vaccine (4vHPV) up to 10 years after the first dose. METHODS: Girls aged 9-13 years were randomized to receive 2D or 3D and were compared with women aged 16-26 receiving 3D at day 1 and months 7, 24, and 120 after the first dose. Antibody levels for HPV6/11/16/18 were evaluated using the competitive Luminex immunoassay (cLIA) and total immunoglobulin G assay. Geometric mean titers (GMTs) and seropositivity rates were compared between the different groups at different time points. Noninferiority of GMT ratios was defined as the lower bound of the 2-sided 95% confidence interval (CI) being greater than 0.5. Kinetics of antibody titers over time among study groups were examined. RESULTS: At 120 months, data from 35 2D girls, 38 3D girls, and 30 3D women were used for analyses. cLIA seropositivity rates were above 95% for all HPV vaccine types and all schedules, except HPV18, with the lowest seropositivity observed among 3D women (60.0%; 95% CI, 40.6%-77.3%). GMT ratios (cLIA) for both 2D and 3D girls were noninferior to 3 doses in women for HPV6/11/16/18. Trends were comparable between assays. CONCLUSIONS: GMTs for HPV6/11/16/18 after 2D or 3D of 4vHPV in girls were noninferior to 3D in adult women up to 120 months postvaccination. This study demonstrates long-term immunogenicity of the 2D HPV vaccine schedule.

Will Infant Hepatitis B Immunization Protect Adults?

Globally, infant hepatitis B virus (HBV) immunization programs are markedly reducing the rate of chronic HBV infections among children <5 years of age. Desirable improvements include increased birth dose coverage and better prevention of perinatal HBV transmission. Follow-up studies show that by the teenage years most of those immunized as infants have lost circulating anti-HBs antibody and some fail to respond to challenge HBV vaccination, implying loss of protection from infection. With high exposure to HBV, such individuals can develop breakthrough HBV infection but this rarely leads to chronic infection, the main goal of prevention programs. While longer-term follow-up studies into adulthood are needed, current evidence does not support a need for booster immunization of otherwise healthy teens or young adults.

Cellular immune responses of older adults to four influenza vaccines: Results of a randomized, controlled comparison.

Cellular immunity is important for protection against the serious complications of influenza in older adults. As it is unclear if newer influenza vaccines elicit greater cellular responses than standard vaccines, we compared responses to 2 standard and 2 newer licensed trivalent inactivated vaccines (TIVs) in a randomized trial in older adults. Non-frail adults ≥ 65 y old were randomly assigned to receive standard subunit, MF59-adjuvanted subunit, standard split-virus or intradermal split-virus TIV. Peripheral blood mononuclear cells (PBMC) harvested pre- and 3-weeks post-vaccination were stimulated with live A/H3N2 virus. PBMC supernatants were tested for interleukin 10 (IL-10) and interferon gamma (IFN-γ), and lysates for granzyme B (GrB). Flow cytometry identified CD4+ and CD8+ T- cells expressing intracellular IL-2, IL-10, IFN-γ, GrB, or perforin. Differences following immunization were assessed for paired subject samples and among vaccines. 120 seniors participated, 29-31 per group, which were well matched demographically. Virus-stimulated PBMCs were GrB-rich before and after vaccination, with minimal increases evident. Immunization did not increase secretion of IFN-γ or IL-10. However, cytolytic effector T-cells (CD8+GrB+perforin+) increased significantly in percentage post-vaccination in all groups, to similar mean values across groups. CD4+GrB+perforin+ T-cells also increased significantly after each vaccine, to similar mean values among vaccines. Vaccination did not increase the low baseline percentages of CD4+ or CD8+ T-cells expressing IFN-γ, IL-2 or IL-10 . In conclusion, participants had pre-existing cellular immunity to H3N2 virus. All 4 vaccines boosted cellular responses to a similar but limited extent, particularly cytolytic effector CD8+ T-cells associated with clinical protection against influenza.

Pertussis and influenza immunisation during pregnancy: a landscape review.

Immunisation during pregnancy is a relatively new strategy, and is currently limited to tetanus, pertussis, and influenza vaccines. None of these vaccines were developed specifically for use in pregnancy, but they provide an effective method of protecting mothers and young infants. In response to increases in pertussis morbidity and mortality among young infants, several countries have recommended universal tetanus, diphtheria, and acellular pertussis immunisation during pregnancy. Similarly, many countries recommend influenza immunisation during pregnancy to reduce the risk of disease for mother and infant. Although scientific evidence to support maternal immunisation against pertussis and influenza is rapidly accumulating, important knowledge gaps remain that need to be addressed by future research, which we have highlighted in this Series paper.

Maternal immunisation: collaborating with mother nature.

Maternal immunisation has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. The success of tetanus, influenza, and pertussis immunisation during pregnancy has led to consideration of additional maternal immunisation strategies to prevent group B streptococcus and respiratory syncytial virus infections, among others. However, many gaps in knowledge regarding the immunobiology of maternal immunisation prevent the optimal design and application of this successful public health intervention. Therefore, we did an innovative landscape analysis to identify research priorities. Key topics were delineated through review of the published literature, consultation with vaccine developers and regulatory agencies, and a collaborative workshop that gathered experts across several maternal immunisation initiatives-group B streptococcus, respiratory syncytial virus, pertussis, and influenza. Finally, a global online survey prioritised the identified knowledge gaps on the basis of expert opinion about their importance and relevance. Here we present the results of this worldwide landscape analysis and discuss the identified research gaps.

Will Infant Hepatitis B Vaccination Protect Into Adulthood?: Extended Canadian Experience After a 2-, 4- and 6-month Immunization Schedule.

BACKGROUND: Hepatitis B virus (HBV) vaccination programs generally target infants to prevent chronic HBV infection and/or preadolescents to reduce transmission in adulthood. To assess whether infant HBV immunization can potentially accomplish both objectives, we measured residual immunity 10-16 years after vaccination in Canadian children. METHODS: A prospective, parallel group, single center study enrolled adolescents given HBV vaccine at 2, 4 and 6 months of age. Exclusion criteria included prior HBV infection and additional vaccinations. At follow-up anti-HBs testing, participants were 10-11 or 15-16 years old; those with <12 mIU/mL anti-HBs by the assay used were challenged with HBV vaccine to assess immune memory-based responsiveness. RESULTS: A total of 137 tested participants were 10-11 and 213 were 15-16 years old, respectively; none had evidence of prior HBV infection. At baseline, 78% of younger and 64% of older participants had <12 mIU/mL anti-HBs (P = 0.006) and were challenged with vaccine: 103/106 (97.2%) younger and 123/135 (91.1%) older participants developed ≥12 mIU/mL anti-HBs (P = 0.06), with geometric mean antibody concentration of 590 (95% confidence interval: 473-737) and 319 mIU/mL (95% confidence interval: 229-445; P = 0.004), respectively. Immune memory loss may have occurred in 3 younger (2.2%) and 12 older children (5.6%; P = 0.06) who were nonresponsive to first but not second vaccine challenge. CONCLUSIONS: After HBV vaccination at 2, 4 and 6 months of age, most adolescents had little or no residual antibody but nearly all responded to HBV challenge, confirming immune memory persistence. However, anamnestic responses were weaker in 15- to 16-year olds and lost in some. Booster responses in 10- to 11-year olds were vigorous in comparison. Extended evaluation of protection is warranted.

Do Dose Numbers Matter?: Evaluation of Differing Infant and Toddler Meningococcal C Conjugate Vaccine Programs in Canadian Children.

BACKGROUND: The diversity of Canadian infant meningococcal C conjugate (MenC) vaccine programs is unique among countries providing MenC vaccines and offers a valuable opportunity to determine the optimal vaccine program. This longitudinal study assessed differences in seroprotection by 3 different vaccine schedules in children two years after receiving either 1 toddler MenC vaccine dose (1 dose), 1 infant and 1 toddler dose (2 doses), or 2 infant and 1 toddler MenC vaccine dose (3 doses). METHODS: Three similar cohorts of healthy infants from 1, 2 and 3 dose program areas were enrolled before to their 12 month toddler dose and vaccinated with MenC-tetanus toxoid (MenC-TT) conjugate vaccine. Sera obtained 2 years later were assayed for serogroup C bactericidal activity using standardized procedures with rabbit as the exogenous complement source. Serum bactericidal activity titers ≥1:8 were considered protective. RESULTS: Results were available for 384 children. Rates of seroprotection at 36 months of age were significantly different between the 1 and 3 dose programs, but confidence intervals overlapped between the 1 and 2 dose programs and between the 2 and 3 dose programs: 1 dose 92% (95% confidence interval: 86%-96%) versus 99% (95%-100%) with 2 doses and 100% (97%-100%) with 3 doses. Geometric mean titers were significantly different at 12.1 (10.8-13.5), 32.4 (28.9-36.2) and 50.6 (45.7-55.9) in the 1, 2 and 3 dose programs, respectively. CONCLUSIONS: At 36 months of age, evidence of seroprotection remained for greater than 90% of participants. Our results indicate that 1 toddler dose or 1 infant plus 1 toddler dose with MenC-TT vaccine provides seroprotection against MenC disease in early childhood.

Hospitalization for Influenza A Versus B.

BACKGROUND: The extent to which influenza A and B infection differs remains uncertain. METHODS: Using active surveillance data from the Canadian Immunization Monitoring Program Active at 12 pediatric hospitals, we compared clinical characteristics and outcomes of children ≤16 years admitted with laboratory-confirmed influenza B or seasonal influenza A. We also examined factors associated with ICU admission in children hospitalized with influenza B. RESULTS: Over 8 nonpandemic influenza seasons (2004-2013), we identified 1510 influenza B and 2645 influenza A cases; median ages were 3.9 and 2.0 years, respectively (P < .0001). Compared with influenza A patients, influenza B patients were more likely to have a vaccine-indicated condition (odds ratio [OR] = 1.30; 95% confidence interval [CI] = 1.14-1.47). Symptoms more often associated with influenza B were headache, abdominal pain, and myalgia (P < .0001 for all symptoms after adjustment for age and health status). The proportion of deaths attributable to influenza was significantly greater for influenza B (1.1%) than influenza A (0.4%); adjusted for age and health status, OR was 2.65 (95% CI = 1.18-5.94). A similar adjusted OR was obtained for all-cause mortality (OR = 2.95; 95% CI = 1.34-6.49). Among healthy children with influenza B, age ≥10 years (relative to <6 months) was associated with the greatest odds of ICU admission (OR = 5.79; 95% CI = 1.91-17.57). CONCLUSIONS: Mortality associated with pediatric influenza B infection was greater than that of influenza A. Among healthy children hosptialized with influenza B, those 10 years and older had a significant risk of ICU admission.

Immunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV-IPV/Hib vaccine in Canadian Aboriginal and non-Aboriginal infants.

This study compared immune responses of healthy Aboriginal and non-Aboriginal infants to Haemophilus influenzae type b (Hib) and hepatitis B virus (HBV) components of a DTaP-HBV-IPV/Hib combination vaccine, 1 month after completing dosing at 2, 4 and 6 months of age. Of 112 infants enrolled in each group, 94 Aboriginal and 107 non-Aboriginal infants qualified for the immunogenicity analysis. Anti-PRP concentrations exceeded the protective minimum (≥0.15 µg/ml) in ≥97% of infants in both groups but geometric mean concentrations (GMCs) were higher in Aboriginal infants (6.12 µg/ml versus 3.51 µg/ml). All subjects were seroprotected (anti-HBs ≥10 mIU/mL) against HBV, with groups having similar GMCs (1797.9 versus 1544.4 mIU/mL, Aboriginal versus non-Aboriginal, respectively). No safety concerns were identified. We conclude that 3-dose primary vaccination with DTaP-HBV-IPV/Hib combination vaccine elicited immune responses to Hib and HBV components that were at least as high in Aboriginal as in non-Aboriginal Canadian infants. Clinical Trial Registration NCT00753649.

Outcomes of invasive meningococcal disease in adults and children in Canada between 2002 and 2011: a prospective cohort study.

BACKGROUND: Neisseria meningitidis causes 500 000 cases of septicemia and meningitis worldwide annually, with approximately 200 cases in Canada each year. Previous studies describe a case-fatality rate of 5%-15% and up to 20% of survivors suffering from long-term disability. METHODS: This study was performed in Canada between 2002 and 2011; the study area included >50% of the country's population. We identified risk factors associated with death and the development of complications in children and adults admitted to hospital with confirmed invasive meningococcal disease (IMD). Clinical information was obtained from hospital records. Risk factors for death and complications were analyzed by univariate and multivariable analyses. RESULTS: Of 868 individuals hospitalized with IMD, there were 73 deaths (8.4%) and 157 (18%) developed complications. The most common complications were hearing loss (5.4%), skin scarring (5.4%), amputation (3.4%), renal dysfunction (2.6%), and seizures (2.5%). Mortality was independently associated with shock (adjusted odds ratio [aOR], 23.30; P<.0001), age (aOR, 1.02 per 1-year increased age; P<.0001), symptom onset within 24 hours of admission (aOR, 1.80; P=.0471), and admission to the intensive care unit (aOR, 0.41; P=.0196). Development of complications was independently associated with seizures (aOR, 4.55; P<.0001), shock (aOR, 3.10; P<.0001), abnormal platelet count (aOR, 2.14; P=.0002), bruising (aOR, 3.17; P=.0059), abnormal white blood cell count (aOR, 0.52; P=.0100), and prior antibiotic exposure (aOR, 0.27; P=.0273). CONCLUSIONS: Outcomes following IMD remain poor in this resource-rich setting in the 21st century. These data identify priorities for clinical management of adults and children with IMD, and provide prognostic information for affected patients and their families and cost-effectiveness analyses for meningococcal vaccine programs.

The impact of the meningococcal serogroup C conjugate vaccine in Canada between 2002 and 2012.

BACKGROUND: Before 2001, the incidence of invasive meningococcal disease (IMD) in Canada was 1.0 per 100 000 per year, with 40% of cases caused by serogroup C organisms. During 2001-2005 all provinces introduced the meningococcal serogroup C conjugate vaccine (MCCV) into their routine infant immunization schedule. METHODS: Active, prospective, population-based surveillance of IMD in children and adults was conducted by the Canadian Immunization Monitoring Program, ACTive (IMPACT) during 2002-2012. Inclusion criteria were admission to hospital and identification of Neisseria meningitidis from a sterile site. Incidence was estimated using population census data from Statistics Canada. RESULTS: Prior to MCCV introduction, serogroup C disease incidence was 0.07-0.25 per 100 000 per year depending on the province. Following vaccine introduction, serogroup C disease decreased to <0.05 per 100 000 per year, with a reduction of 14% per year (P = .0014). A decrease occurred in all provinces, despite differing schedules being implemented. The largest decrease of 83% (from 0.27 to 0.05 per 100 000 per year) occurred in the 15-24 year age group (P = .0100) who were not vaccinated in all provinces. There was no impact on the incidence of nonserogroup C disease over the same period (P = .9811). CONCLUSIONS: MCCV dramatically reduced the incidence of serogroup C IMD in Canada through both direct and indirect effects. The observation that disease incidence decreased with different schedules suggests that the doses at 12 months (common to all provinces) and adolescence (7 of 8 provinces studied) were critical in achieving disease control.

Knowledge, attitudes, beliefs and behaviours of older adults about pneumococcal immunization, a Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network (PCIRN) investigation.

BACKGROUND: Fewer Canadian seniors are vaccinated against pneumococcal disease than receive the influenza vaccine annually. Improved understanding of factors influencing pneumococcal vaccination among older adults is needed to improve vaccine uptake. METHODS: A self-administered survey measuring knowledge, attitudes, beliefs and behaviours about pneumococcal vaccination was administered to a cohort of seniors participating in a clinical trial of seasonal influenza vaccines at eight centers across Canada. Eligible participants were ambulatory adults 65 years of age or older, in good health or with stable health conditions, previously given influenza vaccine. The primary outcome was self-reported receipt of pneumococcal vaccination. Multi-variable logistic regression was used to determine factors significantly associated with pneumococcal vaccine receipt. RESULTS: A total of 863 participants completed questionnaires (response rate 92%); 58% indicated they had received the pneumococcal vaccine. Being offered the vaccine by a health care provider had the strongest relationship with vaccine receipt (AOR 23.4 (95% CI 13.4-40.7)). Other variables that remained significantly associated with vaccine receipt in the multivariable model included having heard of the vaccine (AOR 10.1(95% CI 4.7-21.7)), and strongly agreeing that it is important for adults > 65 to be vaccinated against pneumococcus (AOR 3.3 (95% CI 1.2-9.2)). Participants who were < 70 years of age were less likely to be vaccinated. CONCLUSIONS: These results indicate healthcare recommendation significantly influenced vaccine uptake in this population of older adults. Measures to encourage healthcare providers to offer the vaccine may help increase coverage.

Burden of seasonal influenza in children with neurodevelopmental conditions.

BACKGROUND: Studies have identified certain neurologic and neurodevelopmental conditions (NNC) as risk factors for severe influenza infection. The Canadian National Advisory Committee on Immunization does not currently recognize children with NNC as having a high risk of complicated influenza infection unless their condition compromises handling of respiratory secretions. We describe the burden of influenza in hospitalized children with NNC, focusing on those without potential airway compromise. METHODS: Using multi-year surveillance data obtained by the Canadian Immunization Monitoring Program, Active (IMPACT), we examined presenting signs and symptoms, risk factors and outcomes of children hospitalized with seasonal influenza at 12 Canadian pediatric referral centers. Comparisons were made between children with various NNC and other medical conditions, with and without influenza vaccine indications. The analysis is descriptive with selected comparisons made among groups for important indicators of disease severity. RESULTS: We identified 1991 children hospitalized with influenza over 5 seasons: 293 had NNC, 115 of whom did not have airway compromise or another vaccine indication. The latter group presented with seizures more frequently than those with NNC and a vaccine indication (41.7% vs. 26.4%; P = 0.006) and required intensive care unit admission (20.9% vs. 11.8%; P = 0.02) and mechanical ventilation (14.8% vs. 4.5%; P < 0.001) more often than children without NNC but with a vaccine indication. CONCLUSIONS: The burden of influenza infection in children with NNC, even those whose conditions do not obviously compromise respiratory function, is significant. All children with NNC should be recognized as having a high risk of complicated influenza infection and be targeted to receive influenza immunization.

Approved but non-funded vaccines: accessing individual protection.

Funded immunization programs are best able to achieve high participation rates, optimal protection of the target population, and indirect protection of others. However, in many countries public funding of approved vaccines can be substantially delayed, limited to a portion of the at-risk population or denied altogether. In these situations, unfunded vaccines are often inaccessible to individuals at risk, allowing potentially avoidable morbidity and mortality to continue to occur. We contend that private access to approved but unfunded vaccines should be reconsidered and encouraged, with recognition that individuals have a prerogative to take advantage of a vaccine of potential benefit to them whether it is publicly funded or not. Moreover, numbers of "approved but unfunded" vaccines are likely to grow because governments will not be able to fund all future vaccines of potential benefit to some citizens. New strategies are needed to better use unfunded vaccines even though the net benefits will fall short of those of funded programs. Canada, after recent delays funding several new vaccine programs, has developed means to encourage private vaccine use. Physicians are required to inform relevant patients about risks and benefits of all recommended vaccines, publicly funded or not. Likewise, some provincial public health departments now recommend and promote both funded and unfunded vaccines. Pharmacists are key players in making unfunded vaccines locally available. Professional organizations are contributing to public and provider education about unfunded vaccines (e.g. herpes zoster, not funded in any province). Vaccine companies are gaining expertise with direct-to-consumer advertising. However, major challenges remain, such as making unfunded vaccines more available to low-income families and overcoming public expectations that all vaccines will be provided cost-free, when many other recommended personal preventive measures are user-pay. The greatest need is to change the widespread perception that approved vaccines should be publicly funded or ignored.

Applicability of the Brighton Collaboration Case Definition for seizure after immunization in active and passive surveillance in Canada.

BACKGROUND: The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) receives reports via active syndromic surveillance for selected serious AEFI from the Canadian Immunization Monitoring Program Active (IMPACT) and via targeted passive surveillance from Federal/Provincial/Territorial health jurisdictions. Post-immunization seizure is a target of active and passive surveillance. Since 2009, the revised national AEFI reporting forms enable capture of terms specific to several Brighton Collaboration Case Definitions (BCCD) including generalized seizure and fever. OBJECTIVE: To evaluate feasibility of applying the BCCD for generalized seizure to adverse event following immunization (AEFI) reports collected by IMPACT and targeted passive surveillance (non-IMPACT). METHODS: Reports to CAEFISS coded as seizure in children <2 years of age (vaccination dates 1998-2011) were reviewed retrospectively. A BCCD level (1-5 or unclassifiable) was assigned. The effects of reporting source (IMPACT versus non-IMPACT), seriousness [serious (e.g., hospitalized) versus non-serious], vaccination year (1998-2008 versus 2009-2011), and data submission method to CAEFISS (electronic versus paper) were assessed by stratified analysis. RESULTS: There were 459 IMPACT and 908 non-IMPACT cases analyzed, of which 99.6% and 27%, respectively, were serious reports. The revised reporting form that captured the BCCD components (2009-2011) was associated with increased proportions of IMPACT and non-IMPACT cases meeting the BCCD for generalized seizure. CONCLUSIONS: Incorporating the BCCD components (level of consciousness, motor manifestations and fever ≥38°C) into the national reporting form and guidelines appeared to improve the feasibility of their use in AEFI surveillance. This effect was more pronounced among active syndromic surveillance compared to targeted passive surveillance reports.

Safety, immunogenicity, and tolerability of three influenza vaccines in older adults: results of a randomized, controlled comparison.

To determine if newer influenza vaccines can safely improve seroprotection rates of older adults, we compared three licensed trivalent inactivated vaccines (TIVs) in a randomized, controlled trial with evaluator blinding. Participants were non-frail adults ≥ 65 y old, annually TIV-immunized. Study vaccines included intradermal (IDV), MF59-adjuvanted (ADV) and subunit (TIV) formulations of equal potency and strain composition. Blood was obtained before vaccination (V1) and 21 (V2) and 180 d (V3) afterward and tested by hemagglutination inhibition (HAI) assay. Safety diaries were completed daily by participants and specific tolerability questions were posed regarding injections and symptoms. In total, 911 participants were immunized and 887 (97.4%) completed V3. Groups had similar demographics. General symptom rates post-vaccination were similar among groups. Rates of injection site redness after IDV/ADV/TIV were 75%/13%/13% and rates of pain were 29%/38%/20%, respectively, but each vaccine was well tolerated, with symptoms causing little bother. Baseline antibody titers did not differ significantly among groups but B/Brisbane titers were too high for meaningful response assessments. At V2, seroprotection rates (HAI titer ≥ 40) were highest after ADV, the rate advantage over IDV and TIV being significant at 11.8% and 11.4% for H3N2 and 10.2% and 12.5% for H1N1, respectively. At day 180, seroprotection rates had declined ~25% and no longer differed significantly among groups. While IDV and TIV were also well tolerated, ADV induced modestly higher antibody titers in seniors to influenza A strains at 3 weeks but not 6 mo post-vaccination. Immune responses to IDV and TIV were similar in this population.

Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial.

IMPORTANCE: Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible. OBJECTIVE: To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses. DESIGN, SETTING, AND PATIENTS: Randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%). INTERVENTION: Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. MAIN OUTCOMES AND MEASURES: Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months. RESULTS: The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512-1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36. CONCLUSIONS AND RELEVANCE: Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00501137.

Elevated inflammatory mediators in adults with oculorespiratory syndrome following influenza immunization: a public health agency of Canada/Canadian Institutes of Health Research Influenza Research Network Study.

Oculorespiratory syndrome (ORS) is an infrequent adverse event following influenza vaccination. Its clinical presentation suggests that ORS is an immune-mediated phenomenon, but studies of symptomatic individuals have been few. This study measured cytokine levels in peripheral blood samples following influenza vaccination in those with and without current ORS symptoms. Canadian adults receiving the 2010-2011 seasonal influenza vaccine were recruited and asked to promptly report any adverse effects. ORS symptoms occurring 4 to 48 h after vaccination were identified using previously published criteria. Two blood samples were collected from each subject to measure blood plasma cytokine and hemagglutination inhibition antibody (HAI) titers; visit 1 occurred during the acute disease phase or 4 to 72 h after vaccination for controls, and visit 2 occurred another 21 days postimmunization. Nine ORS cases and 35 controls were enrolled. The median age of ORS cases was 49 years, and 89% were female. Most cases had multiple symptoms, but none required medical care. HAI titers before and after vaccination were similar for the cases and controls. Blood plasma cytokine concentrations did not differ between the ORS cases and controls for most cytokines measured (interleukin 4 [IL-4], IL-5, IL-10, IL-13, IL-1α, IL-8, tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], and IL-17A). However, ORS cases had higher levels of IL-10 and IL-3 than the controls at visits 1 and 2, even after all symptoms had subsided. Persistent higher levels of IL-10 and IL-3 in ORS cases suggest that host factors may have predisposed these individuals to develop ORS following influenza vaccination. Further investigations are warranted, as they might identify subjects who are at risk for ORS prior to vaccination.

Controlling serogroup B invasive meningococcal disease: the Canadian perspective.

With publically funded meningococcal immunization programs established in infants, children and adolescents, Canada is at the forefront of invasive meningococcal disease prevention. The advent of two new serogroup B vaccines that may protect against multiple disease-causing strains offers the potential to reduce endemic disease to very low levels in Canada. Canada likely will be one of the first countries with approval to use recombinant serogroup B vaccine. However, inclusion of these new vaccines into public immunization programs will be decided at the provincial/territorial level, rather than nationally, and may result initially in different immunization schedules throughout the country as we have seen with conjugate meningococcal vaccines. Such heterogeneous use and adoption of new vaccines complicates disease control, but may assist in evaluation of effectiveness. Minimally, it requires regionally specific information. In this article, the authors provide an overview of the Canadian epidemiology, serogroup B vaccine characteristics, potential strain coverage, immunization strategies and remaining postmarketing research questions.