Toll-like receptor 2 activators modulate oral tolerance in mice.

BACKGROUND: Toll-like receptor 2 (TLR2) is a widely expressed pattern recognition receptor critical for innate immunity. TLR2 is also a key regulator of mucosal immunity implicated in the development of allergic disease. TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood. OBJECTIVE: The purpose of this study was to evaluate the impacts of TLR2 expression and TLR2 activation on oral tolerance to food antigens in a murine model. METHODS: Mice were fed ovalbumin (OVA) or peanut butter with or without the addition of low doses of TLR2 activators Pam3 CSK4 or FSL-1. Oral tolerance was assessed by analysing antibody responses after a systemic antigen challenge. OVA-specific Tregs were assessed in the Peyer's patches, mesenteric lymph nodes, and spleen in wild-type and TLR2(-/-) mice. Low-dose Pam3 CSK4 was also tested as an oral adjuvant. RESULTS: Oral tolerance was successfully induced in both wild-type and TLR2(-/-) recipient mice, with an associated regulatory T-cell response. Oral TLR2 activation, with low-dose Pam3 CSK4 or FSL-1, during oral antigen exposure was found to alter oral tolerance and was associated with the development of substantial IgE and IgA responses to foods upon systemic challenge. Low-dose oral Pam3 CSK4 treatment also selectively enhanced antigen-specific IgA responses to oral antigen exposure. CONCLUSIONS AND CLINICAL RELEVANCE: TLR2 is not necessary for oral tolerance induction, but oral TLR2 activation modulates humoral IgE and IgA responses during tolerance development. Low-dose Pam3 CSK4 is also an effective oral adjuvant that selectively enhances IgA production. These observations are pertinent to the optimization of oral allergen immunotherapy and oral vaccine development.

Epidemiology of Clostridioides difficile infection in Canada: A six-year review to support vaccine decision-making.

BACKGROUND: Two vaccines against Clostridioides difficile infections (CDI) are currently in phase III trials. To enable decision-making on their use in public health programs, national disease epidemiology is necessary. OBJECTIVES: To determine the epidemiology of hospital-acquired CDI (HA-CDI) and community-associated CDI (CA-CDI) in Canada using provincial surveillance data and document discrepancies in CDI-related definitions among provincial surveillance programs. METHODS: Publicly-available CDI provincial surveillance data from 2011 to 2016 that distinguished between HA-CDI and CA-CDI were included and the most common surveillance definitions for each province were used. The HA-, CA-CDI incidence rates and CA-CDI proportions (%) were calculated for each province. Both HA- and CA-CDI incidence rates were examined for trends. Types of disparities were summarized and detailed discrepancies were documented. RESULTS: Canadian data were analyzed from nine provinces. The HA-CDI rates ranged from 2.1/10,000 to 6.5/10,000 inpatient-days, with a decreasing trend over time. Available data on CA-CDI showed that both rates and proportions have been increasing over time. Discrepancies among provincial surveillance definitions were documented in CDI case classifications, surveillance populations and rate calculations. CONCLUSION: In Canada overall, the rate of HA-CDI has been decreasing and the rate of CA-CDI has been increasing, although this calculation was impeded by discrepancies in CDI-related definitions among provincial surveillance programs. Nationally-adopted common definitions for CDI would enable better comparisons of CDI rates between provinces and a calculation of the pan-Canadian burden of illness to support vaccine decision-making.

Summary of the NACI Update on Immunization in Pregnancy with Tetanus Toxoid, Reduced Diphtheria Toxoid and Reduced Acellular Pertussis (Tdap) Vaccine.

BACKGROUND: In Canada, pertussis is an endemic and cyclical disease, with peaks occurring at two- to five-year intervals. Although pertussis incidence varies by age group, unvaccinated or undervaccinated infants are at greatest risk of infection and associated complications. Since the last National Advisory Committee on Immunization (NACI) recommendations published in 2014, new evidence on the safety and effectiveness of tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis (Tdap) vaccine administration in pregnancy has become available. OBJECTIVE: To provide guidance on maternal immunization in pregnancy as a strategy to reduce disease incidence and severe outcomes (defined as hospitalization or death) from pertussis infection in infants less than 12 months of age. METHODS: The NACI reviewed evidence on the burden of disease in Canada, vaccine safety and immunogenicity and vaccine effectiveness in jurisdictions that have implemented maternal immunization programs. A total of 59 articles were identified, retrieved and included in the literature review to inform this statement. RESULTS: In the majority of reviewed studies, post immunization increases in antibody levels resulted in more than 90% of women achieving anti-PT levels greater than or equal to 10 IU/ml one month following immunization. In infants, maternal immunization was found to result in increased pertussis antibody concentrations. In the majority of studies, following the receipt of the fourth diphtheria, tetanus and pertussis (DTaP) dose after 15 months of age, no statistically significant differences in antibody levels and avidity were observed between infants whose mothers received Tdap in pregnancy and those whose mothers did not receive Tdap in pregnancy. No major maternal or infant safety issues, including pregnancy outcomes, were reported in the reviewed literature. Effectiveness of maternal Tdap immunization in pregnancy was estimated to be over 90% against pertussis in infants younger than two months of age, with no deaths observed among infants whose mothers received Tdap prior to 36 weeks of pregnancy. Maternal immunization with Tdap in pregnancy also resulted in a reduction in infant disease severity and hospitalization. Vaccine effectiveness was also reported to persist after the receipt of the first three DTaP doses, with immunization in pregnancy resulting in additional protection of up to 70% in children whose mothers received Tdap in pregnancy. CONCLUSION: There is now strong evidence to support the NACI recommendation that immunization with Tdap vaccine should be offered in every pregnancy. This is ideally administered between 27 and 32 weeks of gestation but evidence also supports providing maternal Tdap over a wider range of gestational ages, from 13 weeks up to the time of delivery, in view of programmatic and unique patient considerations.

Updated NACI recommendations for measles post-exposure prophylaxis.

BACKGROUND: Human immune globulin (Ig) products are currently recommended as post-exposure prophylaxis (PEP) for measles in certain susceptible groups. However, successful measles vaccination programs in North America have led to low circulation of measles virus and most blood donors now have vaccine-derived immunity. Concurrently, the concentrations of anti-measles antibodies in human Ig products have shown trends of gradual decline and previously recommended doses and routes of administration may no longer be optimally protective. OBJECTIVES: To review the literature and update recommendations on post-exposure prophylaxis for measles, including dosing and route of administration, for measles Ig PEP in susceptible infants and in individuals who are immunocompromised or pregnant, in order to prevent severe disease. APPROACH: The National Advisory Committee on Immunization (NACI) Measles, Mumps, Rubella, Varicella Working Group reviewed key literature, international practices, and product information for current Ig products pertaining to the optimal dosage and routes of Ig administration for measles PEP. It then proposed evidence-based changes to the PEP recommendations that were considered and approved by NACI. RESULTS: NACI continues to recommend that susceptible immunocompetent individuals six months of age and older, who are exposed to measles and who have no contraindications be given measles-mumps-rubella (MMR) vaccine within 72 hours of the exposure. NACI recommends that for susceptible infants younger than six months of age, if injection volume is not a major concern, intramuscular immunoglobulin (IMIg) should be provided at a concentration of 0.5 mL/kg, to a maximum dose of 15 mL administered over multiple injection sites. Susceptible infants six to 12 months old who are identified after 72 hours and within six days of measles exposure should receive IMIg (0.5 mL/kg) if injection volume is not a major concern. For susceptible contacts who are pregnant or immunocompromised, if injection volume is not a concern, IMIg can be provided at a concentration of 0.5 mL/kg understanding that recipients 30 kg or more will not receive the measles antibody concentrations that are considered to be fully protective. Alternatively, in cases where injection volume is a major concern or for recipients 30 kg or more, intravenous immunoglobulin (IVIg) can be provided at a dose of 400 mg/kg.NACI does not recommend that susceptible immunocompetent individuals older than 12 months of age receive Ig PEP for measles exposure due to the low risk of disease complications and the practical challenges of administration for case and contact management. CONCLUSION: NACI has updated the recommendations for measles PEP to reflect current evidence and best practices in order to prevent severe disease in Canada. Consistent with recommendations in other countries, this includes consideration of off-label use of IVIg in some instances.

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.

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.