Emergency vaccination programs often are needed to control outbreaks of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) on college campuses. Such campaigns expend multiple campus and public health resources. We conducted a randomized, controlled, multicenter, observer-blinded trial comparing immunogenicity and tolerability of an accelerated vaccine schedule of 0 and 21 days to a longer interval of 0 and 60 days for 4-component MenB vaccine (MenB-4C) in students 17–25 years of age. At day 21 after the first MenB-4C dose, we observed protective human serum bactericidal titers >4 to MenB strains 5/99, H44/76, and NZ 98/254 in 98%–100% of participants. Geometric mean titers increased >22-fold over baseline. At day 180, >95% of participants sustained protective titers regardless of their vaccine schedule. The most common adverse event was injection site pain. An accelerated MenB-4C immunization schedule could be considered for rapid control of campus outbreaks.

Abstract 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.

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.

Prophylactic administration of antipyretic/analgesic drugs, started at the time of immunization and repeated 6 and 12 hours later, is sometimes undertaken to reduce postimmunization fever and irritability in infants. Two recent studies showed that such prophylaxis can reduce immune responses to some infant vaccines, warranting judicious use. In contrast, implementing treatment 6 hours or more after immunization had no effect on vaccine responses and would reduce drug exposure of asymptomatic infants.

Human papillomavirus (HPV) vaccination is safe and efficacious in women without human immunodeficiency virus (HIV). Although good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. We enrolled 420 females aged ≥9 years (range, 9–65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (ie, incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher [CIN2+], or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI], 1.1–4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2–4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3–2.6) and of genital warts was 1.0/100PY (95% CI, 0.3–2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02–0.03), 1.5 (95% CI, 1.1–2.0), and 1.2 (95% CI, 0.2–3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY). Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low, and rates of persistent qHPV were lower than in unvaccinated WLWH.

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.

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.

Background: Despite the approved use of live-attenuated intranasal influenza vaccine (LAIV) for seasonal immunization of patients with cystic fibrosis (CF), many questions remain unanswered regarding the timing, duration, and types of adverse events that occur following administration of this vaccine. Methods: In 2012 and 2013, 264 LAIV doses were administered to 198 patients aged 2-19 with CF. Vaccinees were followed prospectively for 55 days after vaccination (day 0) and information on adverse events was collected. Bayesian change-point analysis was used to identify the risk period following LAIV during which participants had a higher risk of reporting adverse events. Multivariable zero-inflated Poisson regression models were then used to estimate the adjusted incidence rate ratio (aIRR) and 95% credible interval (Crl) of reporting each adverse event in the risk period versus the control period. Results: There was a higher risk of reporting serious adverse events (SAEs) (aIRR 1.45, 95% CrI (0.29, 5.17)) and solicited symptoms during days 0-6 of follow-up compared to control period days 7-55. However, most SAEs were not causally related to LAIV and the solicited symptom episodes were brief, usually lasting 1-2 days. There was no increased risk of antibiotic prescriptions for respiratory conditions in the risk vs. control periods (aIRR 0.48, 95% CrI (0.23, 0.91)). Conclusions: Adverse events were most common 0-6 days after LAIV administration but were generally benign and self-limiting. Pulmonary exacerbations did not increase in frequency. (C) 2017 Elsevier Ltd. All rights reserved.

Background: The objective of this study was to explore the effects of viral co-detection in individuals recently vaccinated with the live-attenuated intranasal influenza virus vaccine (LAIV) on the detection of influenza RNA. Methods: Before the 2013–2014 influenza season, nasal swabs were obtained from 59 pediatric participants with cystic fibrosis (CF) and 17 of their healthy siblings immediately before vaccination and 4 times during the week of follow-up. Real-time RT-PCR assays were used to detect influenza RNA. Co-detection of a non-influenza respiratory virus (NIRV) at the time of vaccination was determined by a multiplex RT-PCR assay. Differences in the proportions and rates of influenza detection and their 95% credible intervals (CrI) were estimated. Results: Influenza RNA was detected in 16% fewer participants (95% CrI: −7, 39%) throughout follow-up in the NIRV-positive group compared with the NIRV-negative group (59% vs. 75%). This was also observed in participants with CF alone (66% vs. 74%; RD = 8% 95% CrI: −16, 33%) as well as in healthy participants only (75% vs. 30%; RD = 45%, 95% CrI: −2, 81%). Influenza was detected in NIRV-negative subjects for 0.49 d more compared with NIRV-positive subjects (95% CrI: −0.37, 1.26). Conclusion: The observed proportion of subjects in whom influenza RNA was detected and the duration of detection differed slightly between NIRV- positive and −negative subjects. However, wide credible intervals for the difference preclude definitive conclusions. If true, this observed association may be related to a recent viral respiratory infection, a phenomenon known as viral interference.

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.

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.

Background. We aimed to explore the detection profile of influenza viruses following live-attenuated intranasal influenza vaccination (LAIV) in children aged 2–19 years with and without cystic fibrosis (CF). Methods. Before the 2013–2014 influenza season, flocked nasal swabs were obtained before vaccination and 4 times in the week of follow-up from 76 participants (nCF: 57; nhealthy: 19). Influenza was detected by reverse transcription polymerase chain reaction (RT-PCR) assays. A Bayesian hierarchical logistic regression model was used to estimate the effect of CF status and age on influenza detection. Results. Overall, 69% of the study cohort shed influenza RNA during follow-up. The mean duration of RT-PCR detection was 2.09 days (95% credible interval [CrI]: 1.73–2.48). The odds of influenza RNA detection on day 1 following vaccination decreased with age in years (odds ratio [OR]: 0.82 per year; 95% CrI: 0.70–0.95), and subjects with CF had higher odds of influenza RNA detection on day 1 of follow-up (OR: 5.09; 95% CrI: 1.02–29.9). Conclusion. Despite the small sample size, our results indicate that LAIV vaccine strains are detectable during the week after LAIV, mainly in younger individuals and vaccinees with CF. It remains unclear whether recommendations for avoiding contact with severely immunocompromised patients should differ for these groups.

BACKGROUND: Since January 2012, almost all Canadian provinces have implemented publically funded rotavirus immunization programs. IMPACT had been doing routine active surveillance for rotavirus hospital-izations at pediatric hospitals in 7 provinces since 2005. OBJECTIVES: Determine changes in hospitalization for rotavirus infection pre and post vacination programs. DESIGN/METHODS: Active, surveillance of patients hospitalized for rotavirus infections was conducted by IMPACT from January 1 2010 to December 2015 at 12 paediatric hospitals. Rotavirus hospitalization data was compared for periods pre (2010-2011) and post (2012-2014) implementation of publically funded immunization programs. Six sites were located in jurisdictions that had publically funded programs as of January 2012. RESULTS: Initiation of rotavirus vaccine programs have resulted in a 43% overall reduction in hospitalizations for rotavirus infection in pediat-ric hospitals in Canada with the greatest decreases seen in provinces with programs that were established as of January 2012 where there was a 66% reduction in hospitalizations. Overall, the average yearly number of hospi-talizations for 2012-2014 was 279, compared to 490 in 2010-2011. Six sites with publically funded programs since 2012 had a yearly average of 121.3 cases identified in 2012-2014 compared to an average of 360 cases in 2010-2011. The average yearly number of hospital acquired cases decreased from 78 to 24.7 in sites with vaccine programs whereas sites without increased (26.5 to 33.7 average cases yearly). The proportion of cases occurring in children <2 years was significantly lower in sites with programs (51.6% vs. 72.5%; p<0.0001). In 2012-2014, 63.4% of children were <2 years compared to the period 2010-2011 where 67.7% were <2 years. The seasonal peak in infections has decreased over time, especially in the age groups 6-11 months and 12 to 24 months. CONCLUSION: Publically funded rotavirus vaccine programs have resulted in important reductions in hospitalizations due to community acquired and hospital acquired rotavirus infections in pediatric hospitals in Canada with the greatest decreases seen in provinces with programs that were established as of January 2012. The proportion of children < 2 years hospitalized with rotavirus infection is decreasing at sites with established programs. Given the >85% efficacy of rotavirus vaccine, increasing uptake and delivery throughout Canada could potentially decrease admissions further.

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.

BACKGROUND: Before implementation of the first conjugate IPD vaccine program in 2002, invasive pneumococcal disease (IPD) accounted for most severe, invasive bacterial infections in Canadian children. Conjugate vaccine programs in children were implemented with the expectation that the burden of disease from IPD would improve. OBJECTIVES: To describe the changes in Canadian epidemiology of pediatric IPD before and after the implementation of conjugate pneumo-coccal vaccine programs. DESIGN/METHODS: The Canadian Immunization Monitoring Program, Active (IMPACT) captures all in- and out-patient lab-confirmed IPD cases presenting at its 12 tertiary care pediatric hospitals across Canada. Nurses abstract case details from the hospital chart onto a standardized report form. Case isolates are serotyped at a central reference laboratory. All participating centers have local ethics and/or administrative approvals. RESULTS: From 2000-2014 IMPACT centers identified 3,328 IPD cases. Annual case numbers decreased by 48% (323 to 168) over this time period. Annually, vaccine preventable serotypes accounted for on average 89% (n=288) of cases in the pre-conjugate vaccine era (2000-2003) and 34% (n=56) in the post-13-valent conjugate vaccine era (2011-2014), with 73% (n=41/56) due to serotypes 19A, 3 and 6a. The age distribution of cases shifted upward over the time period with 16% (n=204) of cases occurring in children 5 years of age and older in the pre-vaccine era compared to 32% (n=217) in the post 13-valent vaccine era. This shift was due to decreases in cases occurring in children 0-4 years of age, rather than a significant increase in the number of cases occurring in older children. The most frequent presentation of IPD was radiologic-confirmed pneumonia (n=1119), with complicated pneumonia (pneumonia with empyema or pleural effusion) accounting for 36% (405/1119) of cases, followed by bacteremia only (n=919) and meningitis (n=532). The proportion of cases presenting with complicated pneumonia increased significantly (from 6% -24%; p<0.0001) between the pre-conjugate and post 13-valent conjugate eras. The proportion of cases presenting with meningitis did not change over the time periods (15% pre-conjugate era vs. 16% post-13-valent conjugate era; p=0.46). However, the proportion of meningitis caused by vaccine preventable serotypes decreased significantly (from 85%-26%; p<0.0001). CONCLUSION: The epidemiology of pediatric IPD has changed with the introduction of conjugate vaccine programs. IPD has been reduced by almost 50% in the post-13-valent conjugate vaccine era and vaccine sero-types account for just one-third of cases. However, complicated pneumonia is seen more frequently in the post-13-valent conjugate vaccine era.

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.

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).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 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.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.