Human papillomavirus (HPV) vaccination across a cascade of knowledge, willingness, and uptake among gay, bisexual, and other men who have sex with men in Canada's three largest cities.

BACKGROUND: Some Canadian jurisdictions offer publicly funded HPV vaccine to gay, bisexual, and other men who have sex with men (GBM) aged ≤26 years. We characterized factors associated with being in different stages of HPV vaccination. METHODS: Engage is a sexual health study of GBM in the three largest Canadian cities recruited via respondent driven sampling (RDS). We categorized participants as: (1) unaware of HPV vaccine, (2) undecided/unwilling to get vaccinated, (3) willing to get vaccinated, (4) vaccinated with one or more doses. Our RDS-II weighted analyses used multinomial logistic regression to identify factors associated with being in earlier stages of the cascade compared to Stage 4. RESULTS: Across the cities, 26-40%, 7-14%, 33-39%, and 13-28% were in Stages 1 to 4, respectively. Compared to Stage 4, being in earlier stages of the cascade was associated with bisexual-identification (Stage 1: adjusted odds ratio[aOR] = 2.84, 95% confidence interval[CI] = 1.06-7.62; Stage 2: aOR = 3.09, 95%CI = 1.19-8.05), having immigrated to Canada (Stage 1: aOR = 1.79, 95%CI 1.07-2.99), preference to keep same-sex romantic relationships private (Stage 1: aOR = 1.25, 95% CI = 1.05-1.48; Stage 2: aOR = 1.24, 95%CI = 1.05-1.46), not receiving sexual health information (Stage 1: aOR = 0.31, 95% CI = 0.13-0.71; Stage 2: aOR = 0.27, 95%CI = 0.12-0.64), not accessing a health-care provider (Stage 2: aOR = 0.36, 95%CI = 0.15-0.83), and no past hepatitis A/B vaccination (Stage 1: aOR = 0.16, 95% CI = 0.09-0.30; Stage 2: aOR = 0.18, 95%CI = 0.09-0.35; Stage 3: aOR = 0.38, 95%CI = 0.21-0.61). DISCUSSION: Interventions are needed to reduce social and financial barriers, increase sexual health knowledge, and improve GBM-competent health-care access to increase vaccine uptake among GBM.

Human papillomavirus (HPV) vaccine uptake among a community-recruited sample of gay, bisexual, and other men who have sex with men in the three largest cities in Canada from 2017 to 2019.

INTRODUCTION: In 2015/2016, Canada's largest provinces implemented publicly-funded human papillomavirus (HPV) vaccination programs for gay, bisexual, and other men who have sex with men (GBM) ≤ 26 years old. We sought to describe HPV vaccine uptake among GBM and determine barriers and facilitators to vaccine initiation with a focus on healthcare access and utilization. METHODS: Engage is a cohort study among GBM aged 16 + years in three Canadian cities recruited from 2017 to 2019 via respondent driven sampling (RDS). Men completed a comprehensive questionnaire at baseline. By publicly-funded vaccine eligibility (≤26 years old = eligible for vaccination, ≥27 years old = ineligible), we described HPV vaccine uptake (initiation = 1 + dose, completion = 3 doses) and explored factors associated with vaccine initiation using Poisson regression. All analyses were weighted with the RDS-II Volz-Heckathorn estimator. RESULTS: Across the three cities, 26-35% and 14-21% of men ≤ 26 years and 7-26% and 2-9% of men ≥ 27 years initiated and completed HPV vaccination, respectively. Vaccine initiation was significantly associated with STI/HIV testing or visiting a HIV care specialist in the past six months (≤26: prevalence ratio[PR] = 2.15, 95% confidence interval[CI] 1.06-4.36; ≥27: PR = 2.73, 95%CI 1.14-6.51) and past hepatitis A or B vaccination (≤26: PR = 2.88, 95%CI 1.64-5.05; ≥27: PR = 2.03, 95%CI 1.07-3.86). Among men ≥ 27 years old, vaccine initiation was also positively associated with accessing PrEP, living in Vancouver or Toronto, but negatively associated with identifying as Latin American and increasing age. Vaccine initiation was twice as likely among men ≥ 27 years with private insurance versus no insurance. CONCLUSIONS: Sixty-five to 74% of men eligible for publicly-funded vaccine across the three cities remained unvaccinated against HPV by 2019. High vaccine cost may partly explain even lower uptake among men ≥ 27 years old. Men seeking sexual health care were more likely to initiate vaccination; bundling vaccination with these services may help improve HPV vaccine uptake.

HIV cure research in the time of COVID-19 - Antiretroviral therapy treatment interruption trials: A discussion paper.

This discussion paper addresses the safety of HIV cure studies, particularly those involving stopping antiretroviral therapy, known as an analytic treatment interruption (ATI) in the context of the SARS-CoV-2 pandemic. More than 30 studies listed on ClinicalTrials.gov include an ATI and many others were planned to begin over the next 12 months but most were halted due to the COVID-19 pandemic. We consider the ethics, risks and practical considerations to be taken into account before re-opening HIV cure clinical trials, noting the specific risks of ATI in the context of circulating SARS-CoV-2.

Evaluating the use of whole genome sequencing for the investigation of a large mumps outbreak in Ontario, Canada.

In 2017 Ontario experienced the largest mumps outbreak in the province in 8 years, at a time when multiple outbreaks were occurring across North America. Of 259 reported cases, 143 occurred in Toronto, primarily among young adults. Routine genotyping of the small hydrophobic gene indicated that the outbreak was due to mumps virus genotype G. We performed a retrospective study of whole genome sequencing of 26 mumps virus isolates from early in the outbreak, using a tiling amplicon method. Results indicated that two of the cases were genetically divergent, with the remaining 24 cases belonging to two major clades and one minor clade. Phylogeographic analysis confirmed circulation of virus from each clade between Toronto and other regions in Ontario. Comparison with other genotype G strains from North America suggested that the presence of co-circulating major clades may have been due to separate importation events from outbreaks in the United States. A transmission network analysis performed with the software program TransPhylo was compared with previously collected epidemiological data. The transmission tree correlated with known epidemiological links between nine patients and identified new potential clusters with no known epidemiological links.

Summary of the NACI Update on the recommended use of Human Papillomavirus (HPV) vaccine: Nine-valent HPV vaccine two-dose immunization schedule and the use of HPV vaccines in immunocompromised populations.

BACKGROUND: Human papillomavirus (HPV) infections are the most common sexually transmitted infections. In the absence of vaccination, it is estimated that 75% of sexually active Canadians will have an HPV infection at some point in their lives. HPV vaccine programs were first recommended by Canada's National Advisory Committee on Immunization (NACI) in 2007. In addition to the existing HPV vaccine options in Canada, NACI recently recommended the use of a newly authorized nine-valent HPV (HPV9) vaccine according to a 3-dose immunization schedule for the prevention of HPV types 6-, 11-, 16-, 18-, 31-, 33-, 45-, 52- and 58-related cancers and anogenital warts in females aged 9 to 45 years and males aged 9 to 26 years. New data have emerged evaluating a 2-dose immunization schedule for HPV9 vaccine in males and females, which NACI reviewed in order to provide timely guidance on the possibility of a 2-dose immunization schedule for HPV9 vaccine. Recently, a growing number of studies have also specifically explored the responses of immunocompromised subgroups to HPV vaccines, which also triggered a NACI literature review and updated recommendations on this topic. OBJECTIVES: To review evidence for a 2-dose immunization schedule of the HPV9 vaccine and provide recommendations on vaccine schedule; and to summarize evidence from a recent NACI literature review on the use of HPV vaccines in immunocompromised populations and provide recommendations for HPV vaccine use in these groups. METHODS: The NACI HPV Working Group reviewed results from a clinical trial of HPV9 vaccine administered with a 2-dose immunization schedule in males and females (protocol V503-010) and performed a literature review on the topic of HPV immunization of immunocompromised populations. The NACI literature review and the NACI statement were published separately. RESULTS: Only one study investigated a 2-dose immunization schedule with HPV9 vaccine, a large manufacturer-sponsored randomized controlled trial (protocol V503-010) of good quality. Taken in context of studies with other HPV vaccines, NACI considered this study to be a sufficient evidence base for recommendations. Through a comprehensive literature review, 27 studies were identified for evidence synthesis including reports on vaccine immunogenicity, safety, or both for immunocompromised populations. CONCLUSIONS: Based on the evidence reviewed, NACI issued new recommendations for the use of HPV9 vaccine with a 2-dose immunization schedule at 0, 6-12 months in young females and males and updated the grade of evidence for the use of HPV vaccines in immunocompromised populations.

Predominance of weakly cytotoxic, T-betLowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: implications for HIV infection.

The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8+ T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8+ T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8+ T-cells compared with blood, and in vitro neutralization of TGF-ß partially restored perforin expression in gut CD8+ T-cells. These findings suggest that rectal CD8+ T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues.

Invasive serogroup W Neisseria meningitidis (MenW) in Ontario, Canada shows potential clonal replacement during the period January 1, 2009 to June 30, 2016.

BACKGROUND: In Ontario, serogroup W Neisseria meningitidis (MenW) accounts for a small percentage of all invasive meningococcal disease (IMD) and between 2010 and 2014, only zero to three confirmed cases occurred per year. However, between August 2015 and June 2016, six culture confirmed MenW IMD cases were reported in Ontario. OBJECTIVE: All MenW IMD cases in Ontario between January 1, 2009 and June 30, 2016 were reviewed and the N. meningitidis strains involved were characterized. METHODS: MenW cases were identified in the Integrated Public Health Information System byf Public Health Ontario. MenW isolates were characterized at the National Microbiology Laboratory. RESULTS: Of the thirteen MenW IMD cases, six were due to isolates typed as sequence type (ST)-22 clonal complex (cc), six were of ST-11 cc, and one ST-167 cc. Most (83%) MenW cases due to the ST-22 cc occurred prior to 2012 while all six MenW cases due to ST-11 cc happened since May 2014. The six MenW ST-11 isolates appeared to be clonal. CONCLUSION: It appears that a genetic shift in the invasive MenW isolates has occurred in Ontario in 2014 with the ST-11 clone replacing the traditional ST-22 clone.

Summary of the National Advisory Committee on Immunization's updated recommendations on human papillomavirus (HPV) vaccines: Nine-valent human papillomavirus (HPV) of minimum intervals between doses in the HPV immunization schedule.

BACKGROUND: Human papillomavirus (HPV) infections are the most common sexually transmitted infections, and in the absence of vaccination it is estimated that 75 percent of sexually active Canadians will have an HPV infection at some point in their lives. Quadrivalent (HPV4) and bivalent (HPV2) vaccines have been authorized for use in Canada since 2007 and 2010, respectively. Canada's National Advisory Committee on Immunization (NACI) has previously recommended HPV4 vaccination in males and females according to a three-dose (0, 2, 6 months) or a two-dose (0, 6 months) immunization schedule, or HPV2 vaccination for females according to a three-dose (0, 1, 6 months) or a two-dose (0, 6 months) immunization schedule, depending on the age and health status of the recipient. In February 2015, a nine-valent (HPV9) vaccine (Gardasil®9, Merck Canada Inc.) was authorized for use in Canada for the prevention of HPV types 6-, 11-, 16-, 18-, 31-, 33-, 45-, 52- and 58-related cancers and anogenital warts (AGW) in females aged 9 to 45 years and males aged 9 to 26 years. OBJECTIVES: To summarize evidence on the new HPV9 vaccine and make recommendations for its use in Canada, to review epidemiological data on the relative contribution to disease outcomes of the 5 additional genotypes covered in the HPV9 vaccine, and to clarify acceptable minimum intervals between vaccine doses in either a 2-dose or 3-dose HPV immunization schedule. METHODS: The NACI HPV working group performed literature reviews on the topics of HPV vaccine minimum dose intervals, and the HPV9 vaccine. Vaccine manufacturers provided additional data for review. All evidence was reviewed, rated, and a representative dataset for each trial was reported in evidence tables. A knowledge synthesis was performed, and NACI approved specific evidence-based recommendations, elucidating the rationale and relevant considerations. RESULTS: At the time of the review, only one published peer-reviewed study of HPV9 vaccine was available for inclusion, but information from additional unpublished studies in the form of presentations, posters, and abstracts were shared by the vaccine manufacturer to be appraised.​: Based on the evidence available to date, the HPV9 vaccine is recommended on a three-dose schedule for females aged 9 to 26 years; females aged over 26 years who have not been vaccinated previously or who have not completed the vaccination series; and males aged 9 to 26 years. There is insufficient evidence at this time to recommend a two-dose immunization schedule with HPV9 vaccine, but a clinical trial to assess alternate dosing schedules for HPV9 vaccine is currently underway. The efficacy of HPV9 vaccine in preventing infection and disease related to HPV types 31, 33, 45, 52 and 58 in individuals previously immunized with HPV4 vaccine has not been assessed. In Canada, immunization against HPV types 16 and 18 with HPV2, HPV4 or HPV9 vaccine can prevent approximately 70% of anogenital cancers and 60% of high-risk precancerous cervical lesions. Immunization with either HPV4 or HPV9 vaccine can prevent approximately 90% of AGWs (HPV types 6 and 11). Immunization with HPV9 vaccine can prevent up to an additional 14% of anogenital cancers and up to 30% of high-risk precancerous cervical lesions caused by the additional five HPV types (31, 33, 45, 52 and 58) against which the vaccine protects. The disease burden associated with the five additional genotypes contained in HPV9 vaccine is not equally shared between the sexes, with the additional benefit primarily observed among females.​: In terms of the HPV immunization schedule, there is a paucity of published evidence supporting shortened or flexible minimum intervals for HPV vaccines, compared to ample evidence endorsing the recommended schedules as well as evidence supporting delays in the receipt of booster doses. Assumptions about the immunogenicity and efficacy of shortened 'flexibility range' minimum dose intervals rely heavily on the manufacturer's unpublished data on file and their Health Canada-approved recommendations included in the product monographs. The NACI recommendations and evidence grades based on these results are included below. CONCLUSIONS: In addition to the HPV 6, 11, 16, and 18 strains that can be covered by other HPV vaccines, the HPV9 vaccine is expected to provide further protection by preventing infection and disease related to HPV types 31, 33, 45, 52 and 58. Protecting against these additional strains may prevent up to an additional 14% of anogenital cancers and up to 30% of high-risk precancerous cervical lesions in Canada. Efforts should be made to administer HPV vaccines at the recommended intervals. When an abbreviated schedule is required, minimum intervals between HPV vaccine doses should be met including a minimum interval of 24 weeks between the first and last dose in either a 2-dose or 3-dose schedule.

Assessing vaccine safety within Ontario's Universal Influenza Immunization Program, 2012-2013 to 2014-2015.

BACKGROUND: Influenza vaccine is recommended to prevent influenza-related morbidity and mortality. Post-marketing surveillance of adverse events following influenza vaccine is essential to monitor vaccine safety, inform immunization program planning and evaluation, and build confidence in immunization. OBJECTIVE: To summarize adverse events following immunization (AEFIs) reported after receipt of influenza vaccines administered within the Universal Influenza Immunization Program in Ontario. METHODS: AEFIs following administration of influenza vaccines between September 1, 2012 and August 31, 2015 were extracted from the Integrated Public Health Information System (iPHIS) on September 1, 2015. Events were grouped by provincial surveillance definitions. Reporting rates were calculated using provincial population estimates or net doses distributed as the denominator. The standard World Health Organization definition of serious AEFIs was used. RESULTS: There were 12.1 million doses of influenza vaccine distributed in Ontario and 528 AEFIs reported following influenza vaccines administered over three seasons. The annualized reporting rate was 4.4 per 100,000 doses distributed with a significant decreasing trend over time (p<0.05). The median age was 39.6 years (range six months-96 years); children under four years of age had the highest reporting rate (3.5 per 100,000 population). Disproportionate reporting among females was observed (76.5 percent), most notably in those 18 years and older. The most frequently reported events were injection site reactions (36.2 percent of reports). Others included allergic skin reactions (21.1 percent) and rashes (17.3 percent). Serious AEFIs were rare with a reporting rate of 1.6 per million doses distributed. CONCLUSION: This assessment found a low rate of reported adverse events following influenza vaccines administered in Ontario. Most reported events were mild and resolved completely. The findings were consistent with the very good safety profile of influenza vaccines.

Epidemiology of serogroup C and Y invasive meningococcal disease (IMD) in Ontario, 2000-2013: Vaccine program impact assessment.

OBJECTIVES: A publicly-funded meningococcal serogroup C conjugate vaccine (MCCV) program was introduced in Ontario, in 2004/2005 for 1-year-old children as well as adolescents (approximately 12 years old). In 2009, quadrivalent meningococcal conjugate vaccine (MCV4) replaced MCCV for grade seven students. Our objective was to determine meningococcal vaccine program impact on reported cases of serogroup C and Y invasive meningococcal disease (IMD) at the population level in Ontario, Canada. METHODS: Data were obtained from the Ontario reportable diseases system, the integrated Public Health Information System (iPHIS), and Public Health Ontario Laboratories (PHOL) for 2000-2013. Descriptive epidemiologic analyses, including age-specific rates for age groups based on program eligibility, were conducted. Changes over the 14-year observation period and comparison of pre- and post-program periods for MCCV and MCV4 were assessed. Analyses were conducted using SAS 9.3. RESULTS: There were 161 serogroup C IMD cases and its annual incidence decreased significantly over time (17.2% reduction per year [95% CI: 13.4 to 20.7]). The incidence of serogroup C IMD decreased significantly in children aged 1-17 years in the post-program period, based on age-specific incidence rate ratios (IRRs) and their 95% confidence intervals (CIs). Adolescents 12-16 years had the lowest serogroup C IRR (0.07 [95% CI: 0.01 to 0.55]); the rate decreased more than 14-fold between the pre- and post-periods. There were 187 serogroup Y IMD cases and there was a non-significant 1.6% reduction per year [95% CI: -1.9 to 5.1]) over the surveillance period. Likewise, there was a non-significant decrease in serogroup Y IMD among persons 12-16 years (MCV4 eligible) in the post-program period. CONCLUSIONS: Reductions in serogroup C IMD among program eligible and ineligible age groups suggest both direct and indirect MCCV vaccine program impact. Continued surveillance of IMD in Ontario is important to further assess MCV4 program impact.

HIV eradication symposium: will the brain be left behind?

On 18 July 2014, the National Institute of Mental Health in collaboration with ViiV Health Care and Boehringer Ingelheim supported a symposium on HIV eradication and what it meant for the brain. The symposium was an affiliated event to the 20th International AIDS Conference. The meeting was held in Melbourne, Australia, and brought together investigators currently working on HIV eradication together with investigators who are working on the neurological complications of HIV. The purpose of the meeting was to bring the two fields of HIV eradication and HIV neurology together to foster dialogue and cross talk to move the eradication field forward in the context of issues relating to the brain as a potential reservoir of HIV. The outcomes of the symposium were that there was substantive but not definitive evidence for the brain as an HIV reservoir that will provide a challenge to HIV eradication. Secondly, the brain as a clinically significant reservoir for HIV is not necessarily present in all patients. Consequently, there is an urgent need for the development of biomarkers to identify and quantify the HIV reservoir in the brain. Lastly, when designing and developing eradication strategies, it is critical that approaches to target the brain reservoir be included.

Clinical and demographic factors associated with low viral load in early untreated HIV infection in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: A small subset of HIV-positive adults have low HIV RNA in the absence of therapy, sometimes for years. Clinical factors associated with low HIV RNA in early infection have not been well defined. METHODS: We assessed factors associated with low plasma HIV RNA level at study entry in the Strategic Timing of AntiRetroviral Treatment (START) trial. All START participants had a baseline HIV RNA assessment within 60 days prior to randomization. The key covariables considered for this analysis were race, and hepatitis B virus (HBV) and hepatitis C virus (HCV) status. We assessed factors associated with HIV RNA ≤ 50 and ≤ 400 HIV-1 RNA copies/mL using logistic regression. Because of the strong association between region of randomization and baseline low HIV RNA, analyses were stratified by region. RESULTS: We found that, of 4676 eligible participants randomized in START with a baseline HIV RNA assessment, 113 (2.4%) had HIV RNA ≤ 50 copies/mL at baseline, and a further 257 (5.5%) between 51 and 400 copies/mL. We found that HIV exposure routes other than male homosexual contact, higher high-density lipoprotein (HDL) cholesterol levels, higher CD4 cell counts, and higher CD4:CD8 ratio were associated with increased odds of low HIV RNA. HCV antibody positivity was borderline statistically significantly associated with low HIV RNA. Race and HBV surface antigen positivity were not significantly associated with low HIV RNA. CONCLUSIONS: In a modern cohort of individuals with early untreated HIV infection, we found that HIV exposure routes other than male homosexual contact and higher HDL cholesterol were associated with increased odds of low HIV RNA.

A spot of bother: Why varicella vaccine programs matter.

OBJECTIVE: To evaluate Ontario's provincial varicella vaccination program through analysis of aggregate varicella cases in order to determine whether there has been a decrease in reportable disease burden; and to assess varicella vaccine adverse events following immunization (AEFIs). METHODS: Aggregate varicella cases (1993-2013) were extracted from the reportable disease databases. Pre-program (1993-2004) and post-program (2007-2013) periods were chosen according to implementation of the publicly funded vaccination program. AEFIs following administration of varicella vaccines (2010-2013) were also extracted. Reporting rates were calculated using net doses distributed as the denominator. Serious AEFIs were defined using World Health Organization standards. RESULTS: The incidence of aggregate varicella reports decreased significantly over the study period (from 311.4 to 22.2 cases per 100,000 population in 1993 and 2013, respectively). Incidence also decreased significantly in all age groups between the pre- and the post-program periods with a shift in age distribution towards older individuals in the post-program period. A total of 162 AEFIs following varicella vaccine were reported between 2010 and 2013 for an annualized reporting rate of 14.6 per 100,000 doses distributed. The most common events were rash (37.3%), including eight reports of varicella-like rash (0.7 per 100,000 doses distributed). Ten serious events were reported (0.9 per 100,000 doses distributed), and all vaccine recipients recovered. CONCLUSION: Significant reductions in varicella disease incidence and low AEFI reporting rates were observed with the introduction of the publicly funded varicella vaccine program in Ontario. Continued surveillance is indicated to further assess trends in varicella disease and vaccine safety.

Canadian vaccine research networks: Vaccine safety resources for Canada.

The Public Health Agency of Canada / Canadian Institutes of Health Research Influenza Research Network (PCIRN), established in 2009 to undertake evaluative research to inform public health decision making in Canada, is now being replaced by the Canadian Immunization Research Network (CIRN), which will retain the mandate of PCIRN but expand it to all vaccines including influenza vaccine. CIRN is organized as a network of networks focusing on undertaking research in the areas of vaccine safety, adverse events following immunization (AEFIs), vaccine hesitancy, vaccine effectiveness, and vaccine coverage. CIRN's networks include: a clinical trial network; a laboratory network; a modelling and economics network; a network of social science and humanities researchers; a vaccine safety surveillance network; a hospital-based surveillance network; a clinic network to evaluate serious AEFIs; and a network that links vaccine research capacity in provincial health agencies and departments. PCIRN has contributed to Canada's vaccine safety surveillance system and has facilitated the translation of safety research into policy. Vaccine safety surveillance and research will remain a focus of the newly formed Canadian Immunization Research Network.

Summary of the National Advisory Committee on Immunization's Update on the recommended human papillomavirus (HPV) vaccine immunization schedule.

BACKGROUND: Human papillomavirus (HPV) infections are the most common sexually transmitted infections. In the absence of vaccination, it is estimated that 75% of sexually active Canadians will have a sexually transmitted HPV infection at some point in their lives. Canada's National Advisory Committee on Immunization (NACI) has recommended a three-dose immunization schedule with HPV vaccine for females 9 years of age and older and for males between 9 and 26 years of age, since 2007 and 2012, respectively. OBJECTIVE: To outline the evidence on a two-dose HPV vaccine schedule and to make recommendations for the optimal HPV immunization schedule in Canada. METHODS: NACI reviewed the evidence used by the World Health Organization's (WHO's) Strategic Advisory Group of Experts (SAGE) on Immunization for the two-dose HPV immunization schedule recommended for immunocompetent girls 9 to 14 years of age and conducted an additional review of literature for studies not included in, or published after, the SAGE review. A knowledge synthesis was performed then NACI approved specific recommendations and elucidated the rationale and relevant considerations. RESULTS: Based on the evidence available to date, a two-dose HPV immunization schedule among immunocompetent 9- to 14-year-olds is expected to provide similar protective efficacy compared to a three-dose schedule in immunocompetent individuals aged 9 to 26 years. While all studies reviewed included only females, there is no reason to believe that the data would be different in males, given that data from three-dose trials demonstrates similar immune responses. Administration of two doses of HPV vaccine rather than three may increase acceptability by students, parents and health care professionals alike, and may lead to improved HPV immunization coverage and efficiencies by public health agencies. The duration of protection of either two doses or three doses of HPV vaccine is not yet known; research is encouraged to determine whether there is need for a booster dose. CONCLUSION: Based on the evidence available to date, a two-dose HPV immunization schedule (given at least six months apart) among immunocompetent 9- to 14-year-olds may be considered by individuals and jurisdictions to allow for potential cost savings and other individual and programmatic advantages. A three-dose schedule should be used in individuals 15 years of age and older, as well as immunocompromised individuals and immunocompetent HIV-infected individuals. The new and complete set of current recommendations for HPV vaccines will be published in the updated HPV chapter in the Canadian Immunization Guide in the near future.

Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients.

Chronic inflammation may contribute to human immunodeficiency virus (HIV) persistence through a number of potential pathways. We explored the impact of immunosuppressant therapy on peripheral blood measures of HIV persistence following kidney transplantation. Stored plasma and peripheral blood mononuclear cells prior to transplantation and at weeks 12, 26, 52 and 104 posttransplant were obtained from 91 transplant recipients. In a multivariate model, higher pretransplant plasma HIV RNA level (p < 0.0001) and a longer duration of follow-up posttransplant (p = 0.09) were associated with higher posttransplant plasma HIV RNA levels. A higher baseline HIV DNA (p < 0.0001) was significantly associated with higher HIV DNA levels posttransplant, while higher CD4+ T cell count (p = 0.001), sirolimus use (p = 0.04) and a longer duration of follow-up (p = 0.06) were associated with lower posttransplant HIV DNA levels. The association between sirolimus exposure and lower frequency of cells containing HIV DNA levels posttransplant suggest that the immune-modifying drugs may affect the level of HIV persistence during effect therapy. Future studies of sirolimus as a reservoir-modifying agent are warranted.

A cocoon immunisation strategy against pertussis for infants: does it make sense for Ontario?

Pertussis deaths occur primarily among infants who have not been fully immunised. In Ontario, Canada, an adult booster dose was recently added to the publicly funded immunisation programme. We applied number-needed-to-treat analyses to estimate the number of adults that would need to be vaccinated (NNV) to prevent pertussis disease, hospitalisation and death among infants if a cocoon strategy were implemented. NNV=1/(P(M) X R) + 1/(P(F) X R), where P(M),P(F) (proportion of infants infected by mothers, fathers) were sourced from several studies. Rates of disease, hospitalisation or death (R) were derived from Ontario's reportable disease data and Discharge Abstract Database. After adjusting for under-reporting, the NNV to prevent one case, hospitalisation or death from pertussis was between 500-6,400, 12,000-63,000 and 1.1-12.8 million, respectively. Without adjustment, NNV increased to 5,000-60,000, 55,000-297,000 and 2.5-30.2 million, respectively. Rarer outcomes were associated with higher NNV. These analyses demonstrate the relative inefficiency of a cocoon strategy in Ontario, which has a well-established universal immunisation programme with relatively high coverage and low disease incidence. Other jurisdictions considering a cocoon programme should consider their local epidemiology.

Differential escape patterns within the dominant HLA-B*57:03-restricted HIV Gag epitope reflect distinct clade-specific functional constraints.

UNLABELLED: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE: HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

Prolonged Pertussis Outbreak in Ontario Originating in an Under-immunized Religious Community.

Abstract. BACKGROUND: A prolonged pertussis outbreak began in Ontario in November 2011 in an under-immunized religious community and subsequently spread to the general population and a second religious community in the same region of the province. OBJECTIVE: To compare the epidemiology in the religious communities to that of the general population within the affected jurisdictions. METHODS: The analysis includes cases reported through the integrated Public Health Information System (iPHIS) between November 1, 2011 and April 15, 2013 that met the outbreak case definition. Health unit staff assessed whether cases were members of religious communities through case investigations and collected information on immunization status, treatment and outcomes. RESULTS: A total of 443 confirmed and probable outbreak cases were reported in 7 health units. The outbreak began in one religious community (138 cases), before spreading to the general population in the region (273 cases). A second under-immunized community within the region experienced 32 cases. Thirteen cases were hospitalized and no deaths were reported. Disease peaked earlier in the religious community; cases were significantly younger, more likely to be at high risk for pertussis and more likely to be unimmunized. Among the fully immunized general population, 51% of cases were between 10-14 years and with a median of 5.6 years since their last immunization. CONCLUSION: The epidemiology of pertussis in the under-immunized community is distinct from the general population. Transmission of pertussis to the general community is not unexpected during an outbreak; however, the proportion of cases up to date with immunization warrants further investigation.