Reaching for Precision Healthcare in Finland via Use of Genomic Data.

Concerns over future healthcare capacity along with continuing demands for sustainability call for novel solutions to improve citizens' health and wellbeing through effective prevention and improved diagnosis and treatment. Part of the solution to tackle the challenge could be making the most of the exploitation of genomic data in personalized risk assessment, creating new opportunities for data-driven precision prevention and public health. Presently, the utilization of genomic data in the Finnish healthcare system is limited to a few medical specialty areas. To successfully extend the use of genomic information in everyday healthcare, evidence-based and feasible strategies are needed. The national actions that Finland is taking towards this goal are 1) providing scientific evidence for the utility of genomic information for healthcare purposes; 2) evaluating the potential health-economic impact of implementing precision healthcare in Finland; 3) developing a relevant legal framework and infrastructures for the utilization of genomic information; 4) building a national multidisciplinary expert network bringing together relevant professionals and initiatives to achieve consensus among the different stakeholders on specific issues vital for translating genomic data into precision healthcare; 5) building competence and genomic literacy skills among various target groups; and 6) public engagement (informing and educating the public). Taken together, these actions will enable building a roadmap towards the expedient application of genomic data in Finnish healthcare and promoting the health of our citizens.

Role of Academic Biobanks in Public-Private Partnerships in the European Biobanking and BioMolecular Resources Research Infrastructure Community.

Public-private partnerships (PPP) are an efficient means to advance scientific discoveries and boost the medical innovations needed to improve precision medicine. The increasing number and novel nature of such collaborations is keeping the biomedical field in constant flux. Here we provide an update on PPP development involving academic biobanks in the BBMRI community (the European Biobanking and BioMolecular Resources Research Infrastructure) and report the views on PPP of 20 key players from this field. The interviewed academic representants broadly show interest for their institution to establish PPP and initiate or partner with BBMRI expert centers. The results indicate that PPP has gained foothold in this area of biomedical research, with great promise to facilitate access to samples and data and to improve data interoperability and reproducibility.

Transnational access to large prospective cohorts in Europe: Current trends and unmet needs.

Biobank samples and data from studies of large prospective cohorts (LPC) represent an invaluable resource for health research. Efficient sharing and pooling of samples and data is a central pre-requisite for new advances in biomedical science. This requirement, however, is not compatible with the present scattered and traditional access governance structures, where legal and ethical frameworks often form an obstacle for effective sharing. Moreover, the EU General Data Protection Regulation (GDPR) is demanding increasingly rigorous administration from all those organisations processing personal data. The BBMRI-LPC project (Biobanking and Biomolecular Research Infrastructure - Large Prospective Cohorts) assembled 21 LPCs from 10 countries and two EU-wide multinational cohort networks with a key objective to promote collaborative innovative transnational research proposed by external researchers on the broad field of common chronic diseases, and analyze the gaps and needs involved. BBMRI-LPC organized three scientific calls to offer European investigators an opportunity to gain free of charge transnational access to research material available in the participating cohorts. A total of 11 high-quality research proposals involving multiple prospective cohorts were granted, and the access process in the individual projects carefully monitored. Divergent access governance structures, complex legal and ethical frameworks and heterogeneous procedures were identified as currently constituting substantial obstacles for sample and data transfer in Europe. To optimize the scientific value and use of these research resources, practical solutions for more streamlined access governance in collaborative projects are urgently needed. A number of infrastructure developments could be made to improve time-efficiency in access provision.

A toddler PCV booster dose following 3 infancy priming doses increases circulating serotype-specific IGG levels but does not increase protection against carriage.

BACKGROUND: We compared PCV7 serological response and protection against carriage in infants receiving 3 doses (2, 4, 6 months; 3+0 schedule) to those receiving a booster (12 months; 3+1). METHODS: A prospective, randomized controlled study, conducted between 2005 and 2008, before PCVs were implemented in Israel. Healthy infants were randomized 1:1:1 to receive 3+1, 3+0 and 0+2 (control group; 12, 18 months doses). Nasopharyngeal/oropharyngeal swabs were obtained at all visits. Serum serotype-specific IgG concentrations and opsonic activities (OPA) were measured at 2, 7, 13 and 19 months. This study was registered with Current Controlled Trials, Ltd. ISRCTN28445844. RESULTS: Overall, 544 infants were enrolled: 3+1 (n = 178), 3+0 (n = 178) and 0+2 (n = 188). Post-priming (7 months), antibody concentrations were similar in both groups, except for serotype 18C (higher in 3+0). Post-booster (13, 19 months), ELISA and OPA levels were significantly higher in 3+1 than in 3+0 group. Nasopharyngeal/oropharyngeal cultures were positive for Streptococcus pneumoniae in 2673 (54.3%) visits. Acquisition rates (vaccine and non-vaccine serotypes) were similar for 3+1 and 3+0 groups at 7-30 months and for 0+2 group at 19-30 months. CONCLUSIONS: PCV7 booster after 3 priming doses increased substantially IgG concentrations but did not further reduced vaccine-serotype nasopharyngeal acquisition, suggesting that protection from pneumococcal carriage does not depend primarily on serum IgG.

Serum antibodies to the pneumococcal surface proteins PhtB and PhtE in Finnish infants and adults.

We examined naturally acquired antibodies to pneumococcal vaccine candidate proteins PhtB and PhtE in children during their first 2 years of life. Prior culture-confirmed pneumococcal exposure was shown to induce the development of anti-PhtB and -PhtE antibodies. The anti-PhtB or -PhtE antibody concentrations were not significantly associated with a decreased risk of subsequent pneumococcal acute otitis media.

Colonisation endpoints in Streptococcus pneumoniae vaccine trials.

Evaluating vaccine efficacy for protection against colonisation (VEcol) with bacterial pathogens is an area of growing interest. In this article, we consider estimation of VEcol for colonisation with Streptococcus pneumoniae (the pneumococcus). Colonisation is a common, recurrent and multi-type endpoint that requires both careful definition of the vaccine efficacy parameter and the corresponding method of estimation. We review recent developments in the area and provide practical guidelines for choosing the estimand and the estimation method in trials with a colonisation endpoint. We concentrate on methods that are based on a cross-sectional study design, in which only one nasopharyngeal sample is obtained per study subject.

Design questions for Streptococcus pneumoniae vaccine trials with a colonisation endpoint.

Evaluation of vaccine efficacy for protection against colonisation (VEcol) with Streptococcus pneumoniae and other bacterial pathogens is often based on a cross-sectional study design, in which only one nasopharyngeal sample is obtained per study subject. Here we investigate the feasibility of this study design by investigating a number of practical design problems. Specific questions are related to the timing of colonisation measurement with respect to the time of vaccination, the adjustment for the within-host replacement of vaccine-type colonisation by the non-vaccine type pneumococci, and the impact of multiple serotype colonisation on VEcol estimation. We also discuss the issue of choosing the control vaccine, including comparison of two active pneumococcal vaccines, as well as the sample size and the statistical power of colonisation endpoint trials. In addition, the statistical design with the specific aim to include information about VEcol in the licensure process of new pneumococcal vaccine products is discussed.

Serum IgM antibodies contribute to high levels of opsonophagocytic activities in toddlers immunized with a single dose of the 9-valent pneumococcal conjugate vaccine.

In immunogenicity trials of pneumococcal conjugate vaccines (PCVs), only IgG antibody concentrations to pneumococcal capsular polysaccharides (PPSs) are usually determined, along with the opsonophagocytic activity (OPA) of antipneumococcal antibodies. We aimed to determine the role of both IgG and IgM in OPA in toddlers receiving one dose of 9-valent PCV (PCV9). The IgG and IgM antibody concentrations to PPSs of serotypes 6A, 9V, 14, 19F, and 23F were measured by enzyme immunoassay in sera from toddlers (ages 18 to 35 months) 1 month after a single PCV9 dose. The OPA for the same serotypes was measured by multiplexed opsonophagocytosis assay (MOPA). Further, IgG and IgM concentrations and MOPA were measured to PPS of serotypes 6A, 14, and 19F in sera collected 12 months after vaccination. The detected MOPA titers were high in comparison to the IgG concentrations 1 month after immunization. The IgM concentrations were higher than IgG concentrations for serotypes 6A and 14 (P < 0.001) and as high as IgG for serotypes 9V, 19F, and 23F. Correlation of the IgM antibody concentrations with MOPA (r = 0.35 to 0.65) was stronger compared to that of the IgG antibodies (r = 0.07 to 0.41). The depletion of IgG antibodies in three sets of pooled sera only slightly decreased the OPA activity against serotype 14. At 12 months after immunization, 50 to 100% of serum samples still showed detectable MOPA activity against serotypes 6A, 14, and 19F. Our results suggest that IgM contributes to OPA 1 month after a single PCV9 vaccination in toddlers and that functionally active IgM and IgG antibodies persist for at least a year.

The fundamental link between pneumococcal carriage and disease.

Streptococcus pneumoniae (pneumococcus) is a major cause of worldwide mortality and morbidity, and to a large extent is vaccine-preventable. Nasopharyngeal carriage of pneumococcus precedes disease and is the source of pneumococcal spread between people. The use of vaccine effect on carriage as part of the vaccine licensure and post-vaccine introduction evaluation could facilitate and expand the licensure of new, life-saving pneumococcal vaccines and enable a comprehensive estimate of population effects after vaccine introduction. The authors provide a review of the evidence supporting pneumococcal carriage at the individual level as an immediate and necessary precursor to pneumococcal disease. Based on such a causal link between carriage and disease, the authors emphasize the role of information on pneumococcal carriage in vaccine trials and in public health decision-making.

Association of serotype-specific antibody concentrations and functional antibody titers with subsequent pneumococcal carriage in toddlers immunized with a 9-valent pneumococcal conjugate vaccine.

Association of pneumococcal nasopharyngeal carriage with the concentration and opsonophagocytic activity (OPA) of serum serotype-specific antibodies was determined for toddlers 1 month after immunization with a 9-valent pneumococcal conjugate vaccine. Higher anti-serotype 14 and anti-serotype 19F IgG and anti-serotype 14 IgM correlated with a lowered probability of pneumococcal acquisition. Postvaccination OPA did not correlate with pneumococcal carriage.

Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis.

We evaluated the effect of aging on the functional activity of naturally acquired anti-pneumococcal antibodies, the function of neutrophils in phagocytic killing of opsonized pneumococci, and the complement activity. Opsonic activities of antibodies to all tested pneumococcal serotypes were significantly lower and phagocytic killing of pneumococci by neutrophils was significantly impaired among the elderly, whereas the complement activity was slightly higher in the elderly than in the young adults. The reduced functional activity of serotype-specific antibodies and the compromised function of neutrophils in the opsonophagocytosis of pneumococci are likely to contribute to the increased susceptibility of the elderly to pneumococcal diseases.

Pneumococcal carriage and acute otitis media induce serum antibodies to pneumococcal surface proteins CbpA and PhtD in children.

We assessed the development and role of serum anti-CbpA and -PhtD in early childhood in relation to pneumococcal exposure. Serum IgG concentrations to CbpA and PhtD were measured with enzyme immunoassay in serum samples collected at the ages of 6, 12, 18, and 24 months from 50 healthy children and from 50 adults. Furthermore, antibodies to CbpA, PhtD and the C-terminal fragment of PhtD (PhtD C) were measured in serum samples collected at 12 (N=286) and 18 months (N=259) to evaluate the risk of subsequent pneumococcal acute otitis media (AOM) in relation to antibody concentrations. The increase in anti-CbpA and -PhtD concentrations was related to prior pneumococcal exposure. At 12 and 18 months, in the risk model of pneumococcal AOM adjusted for prior pneumococcal AOM, higher concentrations of anti-CbpA, but not anti-PhtD, were associated with a lowered risk of subsequent pneumococcal AOM. In conclusion, pneumococcal exposure induces the development of serum anti-CbpA and -PhtD in early childhood. Anti-CbpA antibodies may play a role in the prevention of subsequent pneumococcal AOM during the second year of life.

Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins.

Elderly individuals are susceptible to pneumococcal infections. Although factors contributing to the increased susceptibility of the elderly to bacterial infections may be several, compromised immune function, a consequence of normal human ageing, is widely accepted to play a role. We evaluated the effect of ageing on the concentrations of naturally acquired antibodies to pneumococcal capsular polysaccharides (PPS) and protein antigens. The concentrations of immunoglobulin G (IgG) and IgM antibodies to the PPS of serotypes 3, 4, 6B, 9V, 14, and 23F and IgG antibodies to the pneumococcal virulence-associated proteins CbpA, LytC, PhtD and its C-terminal fragment (PhtD C), NanA, PspA fam1, and PspA fam2 were measured by enzyme immunoassay in the sera of younger (30 to 64 years of age) and elderly (65 to 97 years of age) adults. The concentrations of anti-PPS IgG against serotypes 3 and 6B, of anti-PPS IgM against serotypes 3, 4, 6B, 9V, and 23F, and of anti-protein IgG against all tested antigens were significantly lower in the elderly than in younger adults. A stronger decline in anti-PPS antibody concentrations was seen with age in women compared to men, while anti-protein antibody concentrations were mainly similar between the genders. Age, gender, and the nature of the antigen have substantial and varying effects on the antibody concentrations in the sera of adults.

Antibodies to pneumococcal surface protein A families 1 and 2 in serum and saliva of children and the risk of pneumococcal acute otitis media.

BACKGROUND: Pneumococcal surface protein A (PspA) is a highly variable yet cross-reactive protein that exists as 2 major families. We assessed the development of human serum and salivary antibodies against the PspA families 1 (PspA1) and 2 (PspA2) in early childhood and their role in the prevention of pneumococcal acute otitis media (AOM). METHODS: Serum levels of IgG and salivary levels of IgA antibodies to PspA1 and PspA2 were measured by use of enzyme immunoassay from the samples from the Finnish Otitis Media Cohort Study obtained at the ages of 12 months (287 and 160 samples, respectively) and 18 months (258 and 131 samples, respectively). The Cox proportional hazard model was used to evaluate the relative risk (RR) of pneumococcal AOM during the 6 months after sampling relative to concentration of serum or presence of salivary anti-PspA in the samples. RESULTS: Anti-PspA1 and anti-PspA2 concentrations at 12 and 18 months were related to prior culture-confirmed pneumococcal exposure. The concentrations of serum anti-PspA were not significantly associated with the risk of pneumococcal AOM. At 18 months, the presence of salivary anti-PspA was significantly associated with a lower risk of pneumococcal AOM during the 6 months after sampling (RR, 0.27 [95% confidence interval, 0.11-0.69]). CONCLUSIONS: The lowered risk of pneumococcal AOM associated with the presence of salivary anti-PspA at 18 months suggests that mucosal anti-PspA antibodies have a role in the prevention of pneumococcal AOM.

Serum antibodies to pneumococcal neuraminidase NanA in relation to pneumococcal carriage and acute otitis media.

Pneumococcal neuraminidase, NanA, is a pneumococcal vaccine candidate. Prior culture-confirmed pneumococcal contacts were shown to induce serum anti-NanA antibodies during the first 2 years of life. The antibody concentrations at neither 12 nor 18 months were significantly associated with the risk of subsequent pneumococcal carriage or acute otitis media.

Pneumococcal carriage and otitis media induce salivary antibodies to pneumococcal capsular polysaccharides in children.

Mucosal immunity likely plays an important role in the defense against Streptococcus pneumoniae. This study examined whether pneumococcal carriage and acute otitis media induce mucosal antibodies to pneumococcal capsular polysaccharides (Pnc-PSs) of types 1, 6B, 11A, 14, 19F, and 23F. Immunoglobulin (Ig) A, IgG, and secretory (S) Ig anti-Pnc-PS antibodies were measured by enzyme immunoassay in the saliva of children at ages 6, 12, 18, and 24 months and were analyzed in relation to the previous pneumococcal findings. A larger proportion of IgA-positive samples and higher concentrations of type-specific IgA antibodies were detected in samples of children with pneumococci of the given types cultured before sampling from nasopharyngeal samples or middle-ear fluid, compared with children who had cultures negative for pneumococci of the indicated types or of all types. The IgA and S-Ig concentrations correlated strongly, which suggests that the anti-Pnc-PS IgA was secretory. Salivary anti-Pnc-PS IgG was detected only rarely.