Opsonophagocytic activity against Streptococcus pneumoniae in Indigenous and non-Indigenous patients with severe chronic kidney disease immunized with 13-valent pneumococcal conjugate vaccine.

Adults with chronic kidney disease (CKD) are at high risk of pneumococcal infections and recommended to receive pneumococcal immunization. Some studies suggest that previous immunization with 23-valent pneumococcal polysaccharide vaccine (PPV23) may decrease the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13). Via quantitation of serum IgG, IgM, and IgA specific to 7 pneumococcal serotypes (3, 6B, 9V, 14, 19A, 19F, 23F), we recently found that the response to PCV13 in previously PPV23 immunized patients with severe CKD was inferior compared to PPV23 naïve patients. As a follow-up of the previous study, we assessed the titers of opsonizing antibodies specific to 13 vaccine serotypes in sera collected as per the original clinical trial protocol. Opsonophagocytic activity (OPA) titers were determined in 57 previously PPV23-immunized (Group 1) and 72 PPV23-naïve (Group 2) patients pre- and post-PCV13 immunization (days 28 and 365). Pre-immunization, the geometrical mean titers (GMT) for 3/13 serotype-specific antibodies were significantly higher in Group 1 than in Group 2. PCV13 induced a significant GMT rise in both groups; an increase in 5/13 serotype-specific GMTs in Group 1 and 12/13 GMTs in Group 2 was present at one year post-immunization. Fold increase in GMTs by day 28 ranged between 2.4 (serotype 1) and 24.6 (serotype 6A) in Group 1, and between 4.3 (serotype 3) and 67.0 (serotype 6A) in Group 2. The fold increase was significantly larger in Group 2 than in Group 1 for serotypes 1, 4, 7F, and 18C. Patients of Indigenous ethnic background had significantly higher GMT for serotypes 6B and 23F at baseline, and for serotypes 5, 6B, 14, 18C, 19A, 19F, and 23F at Day 28 post-immunization, compared to the non-Indigenous counterpart. Conclusions: Patients with severe CKD developed functionally active pneumococcal antibodies post-PCV13 immunization. Previously administered PPV23 had a negative impact on several serotype-specific OPA responses to PCV13 that lasted for at least one year post-immunization. ClinicalTrials.gov ID: NCT02370069.

Naturally acquired antibodies against 7 Streptococcus pneumoniae serotypes in Indigenous and non-Indigenous adults.

Despite the use of pneumococcal conjugate vaccines for pediatric immunization, North American Indigenous populations continue to experience high burden of pneumococcal infections. Naturally acquired antibodies, which can protect unvaccinated adults against pneumococcal infections, have not previously been studied in Canadian Indigenous people. We analysed concentrations of natural serum IgG, IgM and IgA antibodies specific to 7 serotype-specific capsular polysaccharides (3, 6B, 9V, 14, 19A, 19F and 23F) in 141 healthy individuals (age between 18 and 80 years), including Indigenous adults living in 2 geographical different areas of Ontario, Canada, and non-Indigenous residing in northwestern Ontario. Regardless of the geographical area, concentrations of IgG specific to serotypes 6B, 9V, and 14, IgM specific to 9V, and all serotype-specific IgA were significantly higher in Indigenous study participants as compared to non-Indigenous. The differences are likely attributed to an increased exposure of Indigenous individuals to Streptococcus pneumoniae and/or cross-reactive antigens of other microorganisms or plants present in the environment. Although in non-Indigenous adults concentrations of IgM specific to 9V, 19A, 19F, and 23F significantly decreased with age, this was not observed in Indigenous individuals suggesting that Indigenous people may experience continuous exposure to pneumococci and cross-reactive antigens over the life span. Women had generally higher concentrations of natural IgG and IgM concentrations than men, with more striking differences found in Indigenous adults, potentially associated with larger exposure of women to young children, the major reservoir of pneumococci in communities. Our data suggest that increased rates of pneumococcal infections among Indigenous people are unlikely related to deficiency of naturally acquired antibodies, at least those specific to 7 common serotypes. Determining serological correlates of protection for adults will be essential to identify the groups in need of adult pneumococcal immunizations that may prevent excessive burden of the disease among North American Indigenous people.

Immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine in 23-valent pneumococcal polysaccharide vaccine-naïve and previously immunized adult patients with severe chronic kidney disease.

Individuals with chronic kidney disease (CKD) are at high risk of pneumococcal infections and recommended to receive the 23-valent pneumococcal polysaccharide vaccine (PPV23). Although the 13-valent pneumococcal conjugate vaccine (PCV13) has been found to have higher immunogenicity compared to PPV23 in adults with some immunocompromising conditions, previous PPV23 immunization may decrease the immunogenicity of PCV13. We assessed immunogenicity and safety of PCV13 in 74 PPV23-naïve and 58 previously PPV23-immunized (>1 year ago) patients with severe (stage 4-5) CKD. Serum IgG, IgM, and IgA specific to seven serotypes, i.e. 3, 6B, 9V, 14, 19A, 19F, 23F were quantified pre- and 4 weeks and one year post-immunization. Baseline concentrations for most serotype-specific IgG and IgM, and serotype 3-specific IgA were higher in previously PPV23-immunized compared to PPV23-naïve patients. Immunization with PCV13 significantly increased almost all serotype-specific IgG, all IgA and some IgM; an increase in some serotype-specific IgG and IgM lasted for one year. Fold increases in antibody concentrations and the proportion of individuals with >2-fold increase post-immunization were generally larger in PPV23-naïve than previously immunized patients for most serotype-specific IgG and some IgA. The data show that in patients with CKD who received previous PPV23 immunization over one year ago, the antibody response to PCV13 was inferior compared to pneumococcal vaccine naïve study participants. In both groups, the lowest response to PCV13 was found for serotype 3. Patients of Indigenous ethnic background demonstrated a superior immune response to PCV13 compared to the non-Indigenous counterpart that could partially be related to Indigenous study participants' younger age. Although we found that previous PPV23 immunization could contribute to the more frequent occurrence of systemic adverse events post PCV13 immunization, those did not exceed the mild to moderate range.

The effect of pneumococcal immunization on total and antigen-specific B cells in patients with severe chronic kidney disease.

BACKGROUND: While the 23-valent pneumococcal polysaccharide vaccine (PPV23) is routinely used in Canada and some other countries to prevent pneumococcal infection in adults with chronic kidney disease (CKD), patients develop a suboptimal antibody response to PPV23 due to their immune dysfunction. The 13-valent pneumococcal conjugate vaccine (PCV13) has superior immunogenicity in some categories of immunocompromised adults; however, its effect on the immune response in CKD patients has only been addressed by two recent studies with conflicting results. The effect of PPV23 or PCV13 on B cells in these patients has not been previously studied. We studied the absolute numbers and proportions of B cells and subpopulations in two groups of adult patients with severe CKD pre- and 7 days post-immunization with PCV13: pneumococcal vaccine naïve and previously immunized with PPV23 (over one year ago). RESULTS: PPV23 immunized patients had significantly lower proportions and absolute numbers of class switched memory (CD19 + CD27 + IgM-), as well as lower absolute numbers of IgM memory (CD19 + CD27 + IgM+) and class switched B cells (CD19 + CD27-IgM-) compared to PPV23 naïve patients. Following PCV13 immunization, the differences in absolute numbers of B-cell subpopulations between groups remained significant. The PPV23 immunized group had higher proportions of CD5- B cells along with lower proportions and absolute numbers of CD5+ B cells compared to PPV23 naïve patients both pre- and post-immunization with PCV13. However, previous PPV23 immunization did not have a noticeable effect on the numbers of total IgG or serotype 6B and 14 specific antibody-secreting cells detected 7 days post-immunization with PCV13. Nevertheless, fold increase in anti-serotype 14 IgG concentrations 28 days post-PCV13 was greater in PPV23 naïve than in previously immunized patients. CONCLUSIONS: The results suggest that immunization with PPV23 may result in long-term changes in B-cell subpopulations such as increased prevalence of CD5- B cells and decreased prevalence of class switched memory B cells in the peripheral blood. Because previous immunization with PPV23 in patients with CKD is associated with a significant decrease in the total class switched memory B cells in response to subsequent immunization with PCV13, this may reduce PCV13 immunogenicity in the setting of PPV23 followed by PCV13. TRIAL REGISTRATION: Registered February 24, 2015 at ClinicalTrials.gov (NCT02370069).

Natural immunity against Haemophilus influenzae type a and B-cell subpopulations in adult patients with severe chronic kidney disease.

Individuals suffering from severe chronic kidney disease (CKD) are immunocompromised and therefore highly susceptible to various infections including Haemophilus influenzae type a (Hia), an emerging pathogen in North American Indigenous populations. Immunocompromised Indigenous adults are considered a target for a new Hia vaccine under development. In an attempt to foresee their response to Hia immunization, we studied natural immunity against Hia and B-cell subpopulations in sixty patients with CKD residing in a geographic region with noticeable presence of Hia invasive disease. Serum bactericidal activity (SBA) against Hia, concentrations of IgG and IgM antibodies specific to Hia capsular polysaccharide, and B-cell subpopulations were studied in patients with CKD and 35 healthy controls of the same age. Of the patients with CKD, proportions and absolute numbers of B-cell subpopulations were determined for 28 patients. The patients had lower SBA titres compared to controls. Although no significant differences in anti-Hia IgG or IgM antibody concentrations between control and CKD groups were found, IgM antibody concentrations were higher in Indigenous than non-Indigenous patients. Patients with CKD had a higher proportion of B cells (CD19+), class switched memory B cells (CD19+CD27+IgM-) and a lower proportion of CD19+CD27-IgM- B cells compared to healthy controls. Non-Indigenous patients with CKD had significantly higher proportions of IgM memory B cells and CD19+CD27-IgM- B cells compared to Indigenous patients with no significant difference in absolute numbers. Because 72% of CKD patients had detectable SBA titres and 100% had detectable IgG and IgM antibodies it is possible that a portion of IgM memory B cells and class switched memory B cells are specific for Hia resulting from a natural exposure to the pathogen. The data suggest that a Hia-conjugate vaccine may be immunogenic in adult patients with CKD as it will potentially induce re-activation of immunological memory against Hia.

Characterization of natural bactericidal antibody against Haemophilus influenzae type a in Canadian First Nations: A Canadian Immunization Research Network (CIRN) Clinical Trials Network (CTN) study.

During the last two decades, Haemophilus influenzae serotype a (Hia) emerged as an important cause of invasive disease in Canadian First Nations and Inuit, and Alaskan Native populations, with the highest rates reported in young children. Immunocompetent adults, in contrast to children, do not typically develop invasive Hia disease. To clarify factors responsible for an increased burden of invasive Hia disease in certain population groups we studied serum bactericidal activity (SBA) against Hia and quantified IgG and IgM specific to Hia capsular polysaccharide in healthy adult members of two First Nations communities: 1) with reported cases of invasive Hia disease (Northern Ontario, NO), and 2) without reported cases (Southern Ontario, SO), in comparison to non-First Nations living in proximity to the NO First Nations community, and non-First Nations elderly non-frail Canadians from across the country (total of 110 First Nations and 76 non-First Nations). To elucidate the specificity of bactericidal antibodies, sera were absorbed with various Hia antigens. Naturally acquired SBA against Hia was detected at higher rates in First Nations (NO, 80%; SO, 96%) than non-First Nations elderly Canadians (64%); the SBA titres in First Nations were higher than in non-First Nations elderly Canadians (P<0.001) and NO non-First Nations adults (P>0.05). Among First Nations, SBA was mediated predominantly by IgM, and by both antibodies specific to Hia capsular polysaccharide and lipooligosaccharide. CONCLUSIONS: The SBA against Hia is frequently present in sera of First Nations adults regardless of the burden of Hia disease observed in their community; it may represent part of the natural antibody repertoire, which is potentially formed in this population under the influence of certain epigenetic factors. Although the nature of these antibodies deserves further studies to understand their origin, the data suggest that they may represent important protective mechanism against invasive Hia disease.

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae lipooligosaccharide are present in healthy adult individuals.

Nontypeable Haemophilus influenzae (NTHi), a typical mucosal pathogen largely responsible for respiratory infections and pediatric otitis media, has been increasingly recognized as a significant cause of invasive disease, especially in immunocompromised individuals. Lipooligosaccharide (LOS) is a conserved molecule with an important role in H. influenzae virulence and immune evasion, and it may be considered as a vaccine candidate. However, abilities of H. influenzae LOS to induce protective immune response are poorly understood. The goal of this study was to determine whether antibodies against LOS isolated from H. influenzae strains Eagan, Rd and NTHi 375 are present in the sera of normal individuals. Antigen specific IgG and IgM were studied in sera of 71 and 30 healthy adults, respectively. IgG specific for LOS of all three strains was ubiquitously present in our sample population while IgM specific for Eagan, Rd and NTHi 375 LOS compounds was detected in 37%, 63%, and 40% of samples, respectively. All tested serum samples exhibited bactericidal activity against all three H. influenzae strains; the removal of anti-LOS antibodies from the sera resulted in significant increases in bacterial survival of the corresponding strain. NTHi 375 exhibited the highest serum resistance, whereas the Rd strain was the least resistant. Serum bactericidal activity of anti-LOS antibody was mediated via the classical complement pathway. These findings suggest that in healthy adults, naturally acquired complement-activating anti-LOS antibodies significantly contribute to the overall serum bactericidal activity against both encapsulated and non-encapsulated strains of H. influenzae.

Naturally acquired antibodies against Haemophilus influenzae type a in Aboriginal adults, Canada.

In the post-Haemophilus influenzae type b (Hib) vaccine era that began in the 1980's, H. influenzae type a (Hia) emerged as a prominent cause of invasive disease in North American Aboriginal populations. To test whether a lack of naturally acquired antibodies may underlie increased rates of invasive Hia disease, we compared serum bactericidal activity against Hia and Hib and IgG and IgM against capsular polysaccharide between Canadian Aboriginal and non-Aboriginal healthy and immunocompromised adults. Both healthy and immunocompromised Aboriginal adults exhibited significantly higher bactericidal antibody titers against Hia than did non-Aboriginal adults (p = 0.042 and 0.045 respectively), with no difference in functional antibody activity against Hib. IgM concentrations against Hia were higher than IgG in most study groups; the inverse was true for antibody concentrations against Hib. Our results indicate that Aboriginal adults possess substantial serum bactericidal activity against Hia that is mostly due to IgM antibodies. The presence of sustained IgM against Hia suggests recent Hia exposure.

Activation of innate immune responses by Haemophilus influenzae lipooligosaccharide.

A Gram-negative pathogen Haemophilus influenzae has a truncated endotoxin known as lipooligosaccharide (LOS). Recent studies on H. influenzae LOS highlighted its structural and compositional implications for bacterial virulence; however, the role of LOS in the activation of innate and adaptive immunity is poorly understood. THP-1 monocytes were stimulated with either lipopolysaccharide (LPS) from Escherichia coli or LOS compounds derived from H. influenzae Eagan, Rd, and Rd lic1 lpsA strains. Cell surface expression of key antigen-presenting, costimulatory, and adhesion molecules, as well as gene expression of some cytokines and pattern recognition receptors, were studied. Eagan and Rd LOS had a lower capacity to induce the expression of ICAM-1, CD40, CD58, tumor necrosis factor alpha (TNF-α), and interleukin-1ß (IL-1ß) compared to LPS. In contrast, antigen-presenting (HLA-ABC or HLA-DR) and costimulatory (CD86) molecules and NOD2 were similarly upregulated in response to LOS and LPS. LOS from a mutant Rd strain (Rd lic1 lpsA) consistently induced higher expression of innate immune molecules than the wild-type LOS, suggesting the importance of phosphorylcholine and/or oligosaccharide extension in cellular responses to LOS. An LOS compound with a strong ability to upregulate antigen-presenting and costimulatory molecules combined with a low proinflammatory activity may be considered a vaccine candidate to immunize against H. influenzae.

Transforming health professional education through social accountability: Canada's Northern Ontario School of Medicine.

BACKGROUND: The Northern Ontario School of Medicine (NOSM) has a social accountability mandate to contribute to improving the health of the people and communities of Northern Ontario. NOSM recruits students from Northern Ontario or similar backgrounds and provides Distributed Community Engaged Learning in over 70 clinical and community settings located in the region, a vast underserved rural part of Canada. METHODS: NOSM and the Centre for Rural and Northern Health Research (CRaNHR) used mixed methods studies to track NOSM medical learners and dietetic interns, and to assess the socioeconomic impact of NOSM. RESULTS: Ninety-one percent of all MD students come from Northern Ontario with substantial inclusion of Aboriginal (7%) and Francophone (22%) students. Sixty-one percent of MD graduates have chosen family practice (predominantly rural) training. The socioeconomic impact of NOSM included new economic activity, more than double the School's budget; enhanced retention and recruitment for the universities and hospital/health services; and a sense of empowerment among community participants attributable in large part to NOSM. DISCUSSION: There are signs that NOSM is successful in graduating health professionals who have the skills and desire to practice in rural/remote communities and that NOSM is having a largely positive socioeconomic impact on Northern Ontario.

Immune response to Haemophilus influenzae type b vaccination in patients with chronic renal failure.

Adult chronic renal failure patients undergoing hemodialysis are at an increased risk of invasive Haemophilus influenzae type b (Hib) disease due to the lack of functionally active anti-Hib antibodies. The pediatric Hib polysaccharide-protein conjugate vaccine is highly immunogenic in these patients and can provide protection against invasive Hib infection for at least 1 year.

Risk of invasive Haemophilus influenzae type b (Hib) disease in adults with secondary immunodeficiency in the post-Hib vaccine era.

Prior to the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines, invasive Hib disease affected almost exclusively children. According to some recent studies, in the postvaccine era, adults, the elderly, and immunocompromised persons can be affected more often than children. As the production of type-specific anti-capsular polysaccharide antibodies is the major defense mechanism against Hib, individuals with defects in humoral immune responses have high susceptibility to infections caused by Hib. We hypothesized that nonvaccinated adults with chronic conditions causing immunosuppression may lack protective antibody to Hib. We assessed serum anti-Hib IgG levels and bactericidal activity in 59 patients with chronic renal failure, 30 patients with type 2 diabetes mellitus, 28 patients with chronic obstructive pulmonary disease (COPD), and 20 patients with multiple myeloma compared to 32 healthy controls of similar age. Considering antibody at >0.15 µg/ml as the protective correlate in unvaccinated individuals, we detected subprotective Hib antibody levels in 29% of chronic renal failure, 20% of diabetes, 14% of COPD, and 55% of myeloma patients compared to 3% of healthy controls. Additionally, 70% of myeloma and 58% of chronic renal failure patients did not have detectable serum bactericidal activity against Hib. Among individuals with severe diseases causing secondary immunodeficiency, patients with multiple myeloma and chronic renal failure are at an increased risk of invasive Hib disease. Considering that Hib continues to circulate in the population, this study provides a rationale for the immunization of some adult patients with secondary immunodeficiency with the pediatric Hib vaccine to achieve protective immunity.

Canada's new medical school: The Northern Ontario School of Medicine: social accountability through distributed community engaged learning.

Like many rural regions around the world, Northern Ontario has a chronic shortage of doctors. Recognizing that medical graduates who have grown up in a rural area are more likely to practice in the rural setting, the Government of Ontario, Canada, decided in 2001 to establish a new medical school in the region with a social accountability mandate to contribute to improving the health of the people and communities of Northern Ontario. The Northern Ontario School of Medicine (NOSM) is a joint initiative of Laurentian University and Lakehead University, which are located 700 miles apart. This paper outlines the development and implementation of NOSM, Canada's first new medical school in more than 30 years. NOSM is a rural distributed community-based medical school which actively seeks to recruit students into its MD program who come from Northern Ontario or from similar northern, rural, remote, Aboriginal, Francophone backgrounds. The holistic, cohesive curriculum for the MD program relies heavily on electronic communications to support distributed community engaged learning. In the classroom and in clinical settings, students explore cases from the perspective of physicians in Northern Ontario. Clinical education takes place in a wide range of community and health service settings, so that the students experience the diversity of communities and cultures in Northern Ontario. NOSM graduates will be skilled physicians ready and able to undertake postgraduate training anywhere, but with a special affinity for and comfort with pursuing postgraduate training and clinical practice in Northern Ontario.

Graduates of northern Ontario family medicine residency programs practise where they train.

OBJECTIVE: To examine where graduates of the Northeastern Ontario Family Medicine (NOFM) residency program in Sudbury and the Family Medicine North (FMN) program in Thunder Bay practise after graduation, using cross-sectional and longitudinal analyses. METHODS: Data from the Scott's Medical Database were examined. All physicians who graduated from NOFM and FMN between 1993 and 2002 were included in this analysis. Differences in the location of first practice between NOFM and FMN graduates were tested using chi-squared tests. Logistic regression analyses were used to examine the impact of the training program on a physician's first, as well as continuing, practice location. RESULTS: Between 1993 and 2002, FMN graduates were 4.56 times more likely (95% confidence interval [CI] 2.34-8.90) to practise in rural areas, compared with NOFM graduates, but NOFM graduates were 2.50 times more likely than FMN graduates (95% CI 1.35-4.76) to practise in northern Ontario. There was no statistically significant difference between the graduates of the 2 programs in the likelihood of working in either northern Ontario or a rural area. About two-thirds (67.5%) of all person-years of medical practice provided by NOFM and FMN graduates took place in northern Ontario or rural areas outside the north. CONCLUSION: NOFM and FMN have been successful in producing family physicians to work in northern Ontario and rural areas. Results from this study add to the growing evidence from Canada and abroad that rural or northern medical education and training increases the likelihood that the graduates will practise in rural or northern communities.

Big cities and bright lights: rural- and northern-trained physicians in urban practice.

INTRODUCTION: Rural medical education is increasing in popularity in Canada. This study examines why some family physicians who completed their residency training in northern Ontario decided to practise in urban centres. METHODS: We used a qualitative research method. We interviewed 14 graduates of the Family Medicine North program and the Northeastern Ontario Family Medicine program. The interview transcripts were content-analyzed. RESULTS: There were different pathways leading to urban practice. While some pathways were straightforward, others were more complicated. Most participants offered multiple reasons for choosing to work in urban areas, suggesting that the decision-making processes could be quite complex. Family and personal factors were most frequently mentioned as reasons for choosing the urban option. The needs of the spouse and the children were especially important. Most of the participants had no plans to return to rural medical practice, but even these physicians retained some vestiges of rural practice. CONCLUSION: Most Canadian medical schools now offer some rural medical training opportunities. The findings of this study provide some useful insights that could help medical educators and decision-makers know what to expect and understand how practice location decisions are made by doctors.

The first 25 years of the Northwestern Ontario Medical Programme.

OBJECTIVE: A tracking study of the undergraduate medical students and postgraduate residents who participated in the Northwestern Ontario Medical Programme (NOMP) during its first 25 years (1972-1997) was conducted to search for factors related to physician recruitment to Northwestern Ontario. METHODS: Annual editions of the Canadian Medical Directory were used to determine how many participants returned to practise in Northwestern Ontario. RESULTS: A total of 1982 (84.9%) of the 2335 NOMP participants were located using the Canadian Medical Directory. Of those located, 217 (10.9%) had established practice in Northwestern Ontario. Significantly higher recruitment rates (p < 0.001) were found for postgraduate residents (88/410 [21.5%]) than for undergraduates (95/1445 [6.6%]). Undergraduates who returned for multiple placements were significantly (p < 0.001) more likely to practise in Northwestern Ontario. Furthermore, significant differences in recruitment rates (p < 0.001) were found among the 5 Ontario medical schools. A "snapshot" of 1999 identified that undergraduate medical students and postgraduate residents who undertook a NOMP placement were significantly (p < 0.001) more likely to practise in Northwestern Ontario (odds ratio 7.11, 95% confidence interval 5.11-9.90) than those graduating from Ontario universities who did not experience a NOMP placement. CONCLUSIONS: Analysis of 25 years of student tracking data confirms that NOMP placements were significantly associated with physician recruitment to Northwestern Ontario. Recruitment rates from participation in NOMP were higher for postgraduate residents, undergraduate medical students who returned for multiple placements, and for undergraduate medical students from certain Ontario universities.