Adaptive immune responses to two-dose COVID-19 vaccine series in healthy Canadian adults ≥ 50 years: a prospective, observational cohort study.

To evaluate immune responses to COVID-19 vaccines in adults aged 50 years and older, spike protein (S)-specific antibody concentration, avidity, and function (via angiotensin-converting enzyme 2 (ACE2) inhibition surrogate neutralization and antibody dependent cellular phagocytosis (ADCP)), as well as S-specific T cells were quantified via activation induced marker (AIM) assay in response to two-dose series. Eighty-four adults were vaccinated with either: mRNA/mRNA (mRNA-1273 and/or BNT162b2); ChAdOx1-S/mRNA; or ChAdOx1-S/ChAdOx1-S. Anti-S IgG concentrations, ADCP scores and ACE2 inhibiting antibody concentrations were highest at one-month post-second dose and declined by four-months post-second dose for all groups. mRNA/mRNA and ChAdOx1-S/mRNA schedules had significantly higher antibody responses than ChAdOx1-S/ChAdOx1-S. CD8+ T-cell responses one-month post-second dose were associated with increased ACE2 surrogate neutralization. Antibody avidity (total relative avidity index) did not change between one-month and four-months post-second dose and did not significantly differ between groups by four-months post-second dose. In determining COVID-19 correlates of protection, a measure that considers both antibody concentration and avidity should be considered.

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.

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.

The Immunostimulatory Capacity of Nontypeable Haemophilus influenzae Lipooligosaccharide.

BACKGROUND: We have recently found that lipooligosaccharide (LOS) isolated from encapsulated strains of Haemophilus influenzae (H. influenzae) has strong adjuvant, but diminished pro-inflammatory ability as compared to Escherichia coli lipopolysaccharide (LPS). In this study, we aimed to determine the immunostimulatory capacity of nontypeable/ non-encapsulated H. influenzae (NTHi) LOS by comparing the effect of killed bacteria with LOS isolated from the same strain. METHODS: Following stimulation of human monocytic THP-1 cells with killed NTHi strain 375, or with the corresponding amount of LOS, we studied the protein and gene expression of immunostimulatory and antigen-presenting molecules, cytokines, and innate immune receptors. RESULTS: Stimulation with LOS resulted in lower expression of adhesion (CD54, CD58) as well as costimulatory molecules (CD40, CD86), but in higher expression of antigen-presenting molecules (HLA-DR and HLA-ABC) compared to killed NTHi, whereas killed bacteria induced higher release of both TNF-α and IL-10. The results indicate that while LOS of NTHi has decreased capacity to induce pro-inflammatory responses compared to E. coli LPS or killed NTHi, this LOS has the potential to facilitate antigen presentation. CONCLUSIONS: Considering the important role of NTHi as a respiratory pathogen, and its currently increasing significance in the etiology of invasive infections, LOS deserves further attention as a vaccine antigen, which also has potent adjuvant properties.

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.