Julie A. Bettinger

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.

The changing and dynamic epidemiology of meningococcal disease.

The epidemiology of invasive meningococcal disease continues to change rapidly, even in the three years since the first Meningococcal Exchange Meeting in 2008. Control of disease caused by serogroup C has been achieved in countries that have implemented meningococcal C or quadrivalent meningococcal ACWY conjugate vaccines. Initiation of mass immunization programs with meningococcal A conjugate vaccines across the meningitis belt of Africa may lead to the interruption of cyclical meningococcal epidemics. A meningococcal B vaccination program in New Zealand has led to a decreased incidence of high rates of endemic serogroup B disease. Increases in serogroup Y disease have been observed in certain Nordic countries which, if they persist, may require consideration of use of a multiple serogroup vaccine. The imminent availability of recombinant broadly protective serogroup B vaccines may provide the tools for further control of invasive meningococcal disease in areas where serogroup B disease predominates. Continued surveillance of meningococcal disease is essential; ongoing global efforts to improve the completeness of reporting are required.

Leptospirosis in “Eco-Challenge” Athletes, Malaysian Borneo, 2000

Adventure travel is becoming more popular, increasing the likelihood of contact with unusual pathogens. We investigated an outbreak of leptospirosis in “Eco-Challenge” multisport race athletes to determine illness etiology and implement public health measures. Of 304 athletes, we contacted 189 (62%) from the United States and 26 other countries. Eighty (42%) athletes met our case definition. Twenty-nine (36%) case-patients were hospitalized; none died. Logistic regression showed swimming in the Segama River (relative risk [RR]=2.0; 95% confidence interval [CI]=1.3 to 3.1) to be an independent risk factor. Twenty-six (68%) of 38 case-patients tested positive for leptospiral antibodies. Taking doxycycline before or during the race was protective (RR=0.4, 95% CI=0.2 to 1.2) for the 20 athletes who reported using it. Increased adventure travel may lead to more frequent exposure to leptospires, and preexposure chemoprophylaxis for leptospirosis (200 mg oral doxycycline/week) may decrease illness risk. Efforts are needed to inform adventure travel participants of unique infections such as leptospirosis.

Vaccine hesitancy: An overview

Despite being recognized as one of the most successful public health measures, vaccination is perceived as unsafe and unnecessary by a growing number of individuals. Lack of confidence in vaccines is now considered a threat to the success of vaccination programs. Vaccine hesitancy is believed to be responsible for decreasing vaccine coverage and an increasing risk of vaccine-preventable disease outbreaks and epidemics. This review provides an overview of the phenomenon of vaccine hesitancy. First, we will characterize vaccine hesitancy and suggest the possible causes of the apparent increase in vaccine hesitancy in the developed world. Then we will look at determinants of individual decision-making about vaccination.

The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000–2007

Active surveillance was conducted by the 12 centers of the Canadian Immunization Monitoring Program, Active from 2000-2007 in children 16 years of age and younger to determine the influence of 7-valent pneumococcal conjugate immunization programs on the prevalence, serotype and antibiotic resistance patterns of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae. The absolute number of reported IPD cases decreased 48% (p<0.01) over the 8-year period and 56% (p<0.01) in children 0-4 years of age. The absolute number of reported IPD cases caused by serotypes in the conjugate vaccine decreased 87.5% (p<0.01) overall and 92% (p<0.01) in children 0-4 years. Although 6 non-vaccine serotypes increased over time, only serotype 19A increased significantly (p<0.01). Overall, the proportion of penicillin resistant isolates remained unchanged at 17%. Cefotaxime/ceftriaxone resistance remained unchanged at 2% of isolates annually. Universal pneumococcal conjugate infant immunization programs have dramatically decreased cases of invasive pneumococcal disease.

HIV-Exposed Uninfected Infants are at Increased Risk for Severe Infections in the First Year of Life.

HIV-exposed uninfected (HEU) infants have higher infectious morbidity than HIV-unexposed uninfected (HUU) infants. We present the clinical outcomes from a pilot cohort study of 27 HEU and 28 HUU infants. In the absence of infant malnutrition or advanced maternal HIV, HEU infants experienced a 2.74 (0.85-8.78) times greater risk of hospitalization in the first year.

Diversity of Canadian meningococcal serogroup B isolates and estimated coverage by an investigational meningococcal serogroup B vaccine (4CMenB).

BACKGROUND In collaboration with the Canadian Immunization Monitoring Program Active (IMPACT), the National Microbiology Laboratory, the UK Health Protection Agency and Novartis Vaccines, we tested the potential of an investigational 4-component meningococcal B vaccine (4CMenB) to cover Canadian strains circulating from 2006 to 2009. METHODS IMPACT meningococcal surveillance is population based and includes over 50% of Canadian adults and children. All isolates were characterized by Meningococcal Antigen Typing System (MATS) and sequencing for factor H-binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA). RESULTS In total, 157 isolates were tested. Overall, 4CMenB MATS predicted strain coverage was 66% (95% CI: 46-78%), with 26%, 29% and 11% of strains covered by one, two and three vaccine antigens, respectively. The coverage of each antigen was as follows: 13% PorA, 1% NadA, 52% fHbp and 51% NHBA. The majority of strains for clonal complex (cc) 41/44 and cc60 were covered by NHBA; the majority of strains for cc269 and cc32 were covered by fHbp and NHBA. Coverage for two prevalent strains (sequence type (ST)-269 and ST-154) was 95% and 100%, respectively. CONCLUSIONS 4CMenB has the potential to protect against a significant proportion of Canadian invasive MenB strains.

Pandemic influenza in Canadian children: a summary of hospitalized pediatric cases.

A total of 324 pandemic H1N1 cases were reported to the Immunization Monitoring Program, Active from May 1, 2009 to August 31, 2009. As of August 31, 2009, case details were available for 73% (n=235) of these cases. The median age was 4.8 years and 69% of children were older than 2 years of age. In total, 95 (40%) of children were previously healthy. The proportion with an underlying health condition increased with age. Close to 50% of children received antiviral medication. Two children died from the infection. The pediatric risk groups affected and course of disease caused by pandemic H1N1 appear similar to seasonal influenza.

The impact of childhood meningococcal serogroup C conjugate vaccine programs in Canada.

Background: Conjugate meningococcal vaccines may decrease the incidence of disease. The staggered implementation of universal childhood meningococcal C conjugate (MenC) immunization programs across Canada offers an opportunity to evaluate the influence of these programs. Methods: From 2002 to 2006, we conducted active, population-based surveillance for adult and pediatric hospital admissions related to meningococcal infections at the 12 centers of the Canadian Immunization Monitoring Program, Active (IMPACT), in collaboration with local public health officials. Results: A total of 376 cases were reported during the 5 years of surveillance. Yearly totals were as follows: 96 in 2002, 73 in 2003, 81 in 2004, 58 in 2005, and 68 in 2006. Case fatality was 9.3% and adults had a significantly higher case fatality rate than children. Average incidence per 100,000 was 0.62 (95% confidence interval [CI]: 0.50–0.76) in 2002 and 0.42 (95% CI: 0.32–0.53) in 2006. The highest rates were in children age 0 to 4 years, followed by adolescents age 15 to 19 years. Incidence of group C disease decreased significantly during the 5 years from 0.23 (95% CI: 0.16–0.32) in 2002 to 0.08 (95% CI: 0.04–0.14) in 2006, whereas incidence remained stable for groups B, Y, and W135. The decrease in group C disease was seen in provinces that first implemented MenC immunization programs. Conclusions: A substantial decrease in group C incidence occurred in provinces with early MenC immunization programs. Serogroup C incidence remained stable in provinces without MenC programs. We found no evidence of serogroup replacement.

Influenza vaccination in paediatric nurses: Cross-sectional study of coverage, refusal, and factors in acceptance

BACKGROUND Influenza vaccination among health-care workers is poor, and the effectiveness of hospital vaccination programs remains unclear. Little is known about the effectiveness of intensive evidence-based vaccination programs in nursing staff. We determined whether the recommended vaccination rate could be achieved among paediatric nurses during an intensive promotional program for influenza vaccination. We also sought to identify the reasons for which nurses refuse the influenza vaccine and predictors of future vaccination intent. METHODS We offered influenza vaccination to nursing staff during an influenza season through a multi-component program that included intensive promotional activities. We analysed vaccination data to determine uptake rates. In a cross-sectional survey, self-administered questionnaires were distributed to all nurses with patient contact during that season. The questionnaire evaluated their vaccine use, site of work, absenteeism and physician visits due to respiratory illness, vaccination intent for the subsequent influenza season, and other items. We surveyed vaccinated nurses regarding their program experiences and the frequency and severity of adverse reactions. Unvaccinated nurses were asked their reasons for refusing vaccination. Multiple logistic-regression analysis was conducted to identify variables that predicted the likelihood of future vaccine acceptance. RESULTS More than 75% (895/1,182) of applicable nurses were vaccinated in the program. The questionnaire response rate was nearly 48% (585/1,230). Vaccination in the program during the current season (odds ratio [OR] 101.99, 95% confidence interval [CI] 52.54-197.98), program convenience (OR 199.19, 95% CI 98.01-404.11), and a physician visit for respiratory illness (OR 2.44, 95% CI 1.29-4.61) were found to be independent predictors of intent to receive the vaccine the following season. A lack of perceived personal need was the most common reason for vaccine refusal, given in 30% (77/258) of unvaccinated respondents. CONCLUSIONS Adequate coverage of nurses is achievable during an intensive voluntary immunisation program against influenza, using best-known practices. Perceived lack of personal benefit is a major deterrent, while program convenience and previous vaccination strongly predict future vaccine acceptance. Our findings support interventions that improve the convenience of hospital immunisation programs for influenza, particularly those that are aimed at nurses and that promote vaccine efficacy and benefits.