G. De Serres

Epidemiology of varicella zoster virus infection in Canada and the United Kingdom

Many countries are currently studying the possibility of mass vaccination against varicella. The objective of this study was to provide a comprehensive picture of the pre-vaccine epidemiology of the varicella zoster virus (VZV) to aid in the design of immunization programs and to adequately measure the impact of vaccination. Population-based data including physician visit claims, sentinel surveillance and hospitalization data from Canada and the United Kingdom were analysed. The key epidemiological characteristics of varicella and zoster (age specific consultation rates, seasonality, force of infection, hospitalization rates and inpatient days) were compared. Results show that the overall epidemiology of varicella and zoster is remarkably similar between the two countries. The major difference being that, contrary to Canada, the epidemiology of varicella seems to be changing in the United Kingdom with an important decrease in the average age at infection that coincides with a significant increase in children attending preschool. Furthermore, differences exist in the seasonality between the United Kingdom and Canada, which seem to be primarily due to the school calendar. These results illustrate that school and preschool contact patterns play an important role in the dynamics of varicella. Finally, our results provide baseline estimates of varicella and zoster incidence and morbidity for VZV vaccine effectiveness and cost-effectiveness studies.

Modelling the impact of immunization on the epidemiology of varicella zoster virus

The objective of this study was to develop and apply a dynamic mathematical model of VZV transmission to predict the effect of different vaccination strategies on the age-specific incidence and outcome of infection. To do so a deterministic realistic age-structured model (RAS) was used which takes account of the increased potential for transmission within school aged groups. Various vaccine efficacy scenarios, vaccine coverages and vaccination strategies were investigated and a sensitivity analysis of varicella incidence predictions to important parameters was performed. The model predicts that the overall (natural and breakthrough) incidence and morbidity of varicella would likely be reduced by mass vaccination of 12-month-old children. Furthermore, adding a catch-up campaign in the first year for 1-11 year olds seems to be the most effective strategy to reduce both varicella incidence and morbidity (in the short and long term), though with the possible detrimental effect of increasing the incidence of zoster.

The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials.

The test-negative design (TND) is an efficient form of case-control study commonly applied to influenza vaccine effectiveness (VE) estimation. TND validity is predicated on the core assumption that the intervention (vaccine) has no effect on other non-targeted aetiologies resulting in similar illness/disease. Here we verify this core assumption and compare efficacy estimates derived by the TND versus classical per-protocol analysis of four datasets obtained from randomised placebo-controlled clinical trials (RCT) of the live attenuated influenza vaccine (LAIV) in children ≤7 years-old and the elderly ≥60 years-old. We further assess generalisability of the TND approach in two other RCT datasets to evaluate monoclonal antibody in the prevention of respiratory syncytial virus (RSV) hospitalisation. Efficacy estimates and their confidence intervals were virtually identical for per-protocol RCT versus TND analyses of LAIV and also for RSV monoclonal antibody. Neither LAIV nor monoclonal antibodies affected the risk of disease aetiologies that were not specifically targeted by the respective interventions (e.g. other respiratory viruses). This study validates the core assumption of the TND approach for influenza vaccine efficacy estimation and confirms the accuracy and precision of its estimates compared to the gold standard of classic per-protocol RCT analysis of the same data sets. The TND approach is generalisable for other conditions such as RSV for which the core assumption is also met. However, when used in observational studies, the TND, like all designs, still requires assessment for bias and confounding that may exist in the absence of randomised participation and blinded follow-up.

Interim estimates of 2014/15 vaccine effectiveness against influenza A(H3N2) from Canada's Sentinel Physician Surveillance Network, January 2015.

The 2014/15 influenza season to date in Canada has been characterised by predominant influenza A(H3N2) activity. Canadas Sentinel Physician Surveillance Network (SPSN) assessed interim vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza A(H3N2) infection in January 2015 using a test-negative case-control design. Of 861 participants, 410 (48%) were test-positive cases (35% vaccinated) and 451 (52%) were test-negative controls (33% vaccinated). Among test-positive cases, the majority (391; 95%) were diagnosed with influenza A, and of those with available subtype information, almost all influenza A viruses (379/381; 99%) were A(H3N2). Among 226 (60%) A(H3N2) viruses that were sequenced, 205 (91%) clustered with phylogenetic clade 3C.2a, considered genetically and antigenically distinct from the 2014/15 A/Texas/50/2012(H3N2)-like clade 3C.1 vaccine reference strain, and typically bearing 10 to 11 amino acid differences from the vaccine at key antigenic sites of the haemagglutinin protein. Consistent with substantial vaccine mismatch, little or no vaccine protection was observed overall, with adjusted VE against medically attended influenza A(H3N2) infection of ?8% (95% CI: ?50 to 23%). Given these findings, other adjunct protective measures should be considered to minimise morbidity and mortality, particularly among high-risk individuals. Virus and/or host factors influencing this reduced vaccine protection warrant further in-depth investigation. .

Analysis of varicella vaccine breakthrough rates: implications for the effectiveness of immunisation programmes.

The objective of this study was to quantify key parameters describing varicella zoster virus (VZV) vaccine efficacy. To do so a mathematical model was developed to represent breakthrough cases as a function of time after vaccination in vaccine efficacy trials. Efficacy parameter sets were identified by fitting the predicted annual number of breakthrough infections with that observed in three clinical trials chosen to represent the plausible range of vaccine efficacy. Results suggest that varicella vaccination seems to result in a high proportion of individuals who are initially totally protected (97% for the base-case). However, individuals lose full protection relatively rapidly (3% per year for the base-case). Once total protection has waned individuals have a high probability of developing a breakthrough infection if exposed to varicella (73% of the probability in unvaccinated susceptibles for the base-case). Results also highlight that vaccine efficacy parameters should be estimated concurrently to take into account dependencies between parameters.

Interim estimates of 2013/14 vaccine effectiveness against influenza A(H1N1)pdm09 from Canada s sentinel surveillance network, January 2014.

The 2013/14 influenza season to date in Canada has been characterised by predominant (90%) A(H1N1)pdm09 activity. Vaccine effectiveness (VE) was assessed in January 2014 by Canadas sentinel surveillance network using a test-negative case-control design. Interim adjusted-VE against medically-attended laboratory-confirmed influenza A(H1N1)pdm09 infection was 74% (95% CI: 58-83). Relative to vaccine, A(H1N1)pdm09 viruses were antigenically similar and genetically well conserved, with most showing just three mutations across the 50 amino acids comprising antigenic sites of the haemagglutinin protein.

Measles vaccine efficacy during an outbreak in a highly vaccinated population: incremental increase in protection with age at vaccination up to 18 months.

During a large measles outbreak in Quebec City in 1989, two investigations conducted in parallel evaluated the relative risk of measles and measles vaccine effectiveness with respect to age at vaccination. The study was a school-based case-control study including 563 cases and 1126 classmate controls. The second was a cohort study of the siblings of school cases including 493 siblings aged between 1 and 19 years. The relative risks (RR) of measles were similar in both settings and the trend towards increased vaccine efficacy with increasing age at vaccination was highly significant (P < 0.001). Vaccine efficacy rose from 85% in children vaccinated at 12 months of age to > or = 94% in those vaccinated at 15 months and older. Even for children vaccinated at or after 18 months of age, the RR of measles was reduced when compared with children vaccinated between 15 and 17 months of age (RR 0.61, CI 95% 0.33-1.15). Small changes in the timing of initial measles vaccination can have a major impact on vaccine efficacy.

Comparative immunogenicity under field conditions of two recombinant hepatitis B vaccines in 8–10-year-old children

The immunogenicity of two hepatitis B vaccines was compared in 8-10-year-old children immunized in a school program. One year apart, 1129 children received Engerix-B 10 microg vaccine (EB), and 1126 received Recombivax-HB 2.5 microg (RB), following the 0, 1, 6 schedule. Blood samples were collected one month after the third dose. Anti-Hbs were measured by commercial radioimmunoassay. In the EB group, 99.1% of the children seroconverted (>/=2 IU/l) compared to 99.7% in the RHB group (p=0.09). The seroprotection rate (>/=10 IU/l) was similar for both groups: 98.9% in the EB group and 99.2% in the RB group (p=0.66). However, GMCs of anti-HBs were higher in children given EB compared to those given RB (7307 vs. 3800 mIU/ml, p<0.0001). This study showed that both vaccines were highly immunogenic, in the course of a regular field immunization program. However, the difference observed in the antibody levels attained according to the vaccine may play a role in the long-term protection of these children.

Rapid surveillance for health events following a mass meningococcal B vaccine program in a university setting: A Canadian Immunization Research Network study.

An outbreak of Neisseria meningitidis serotype B infection occurred at a small residential university; public health announced an organizational vaccination program with the 4-component Meningococcal B (4CMenB) vaccine (Bexsero(TM), Novartis/GlaxoSmithKline Inc.) several days later. Since there were limited published data on reactogenicity of 4CMenB in persons over 17years of age, this study sought to conduct rapid surveillance of health events in vaccinees and controls using an online survey. Vaccine uptake was 84.7% for dose 1 (2967/3500) and 70% (2456/3500) for dose 2; the survey response rates were 33.0% (987/2967) and 18.7% (459/2456) in dose 1 and dose 1 recipients respectively, and 12% in unvaccinated individuals (63/533). Most students were 20-29years of age (vaccinees, 64.0%; controls, 74.0). A new health problem or worsening of an existing health problem was reported by 30.0% and 30.3% of vaccine recipients after doses 1 and 2 respectively; and by 15.9% of controls. These health problems interfered with the ability to perform normal activities in most vaccinees reporting these events (74.7% post dose 1; 62.6% post dose 2), and in 60% of controls. The health problems led to a health care provider visit (including emergency room) in 12.8% and 14.4% of vaccinees post doses 1 and 2, respectively and in 40% of controls. The most common reactions in vaccinees were injection site reactions (20.6% post dose 1, 16.1% post dose 20 and non-specific systemic complaints (22.6% post dose 1, 17.6% post dose 2). No hospitalizations were reported. An online surveillance program during an emergency meningococcal B vaccine program was successfully implemented, and detected higher rates of health events in vaccinees compared to controls, and high rates of both vaccinees and controls seeking medical attention. The types of adverse events reported by young adult vaccinees were consistent with those previously.

Knowledge, attitudes, beliefs, and behaviors of university students, faculty, and staff during a meningococcal serogroup B outbreak vaccination program

OBJECTIVES During an outbreak of invasive meningococcal B disease on a university campus, we explored the knowledge, attitudes, beliefs, and behaviors of members of the university community in relation to the disease, the vaccine, and the vaccination program. DESIGN All students, faculty and staff were invited by email to participate in a 71-item online survey, which was administered after completion of the mass clinics for the first and second doses of a meningococcal B vaccination program. RESULTS A total of 404 individuals responded to the survey; 75.7% were students. Knowledge about meningococcal disease and vaccine was generally high; more than 70% correct responses were received on each knowledge question except for one question about the different meningococcal serogroups. Gender (female) and higher knowledge scores were significantly associated with either being immunized or intending to be immunized (p<0.05). Positive attitudes about immunization, concern about meningococccal infection, a sense of community responsibility, and trust in public health advice also correlated with being vaccinated or intending to be vaccinated (p<0.05). CONCLUSIONS A successful mass vaccination program in a Nova Scotia university was associated with high levels of knowledge, positive attitudes toward vaccination, and positive attitudes toward public health recommendations.