Background: The incidence of community-acquired pneumonia and lower respiratory tract infection rises considerably in later life. Immunoglobulin M (IgM) antibody levels to pneumococcal capsular polysaccharide are known to decrease with age; however, whether levels of IgM antibody to pneumococcal proteins are subject to the same decline has not yet been investigated. Methods: This study measured serum levels and binding capacity of IgM antibody specific to the pneumococcal surface protein A (PspA) and an unencapsulated pneumococcal strain in serum isolated from hospital patients aged < 60 and ≥ 60, with and without lower respiratory tract infection. A group of young healthy volunteers was used as a comparator to represent adults at very low risk of pneumococcal pneumonia. IgM serum antibody levels were measured by enzyme- linked immunosorbent assay (ELISA) and flow cytometry was performed to assess IgM binding capacity. Linear regression and one-way analysis of variance (ANOVA) tests were used to analyse the results. Results: Levels and binding capacity of IgM antibody to PspA and the unencapsulated pneumococcal strain were unchanged with age. Conclusions: These findings suggest that protein-based pneumococcal vaccines may provide protective immunity in the elderly. Trial registration: The LRTI trial (LRTI and control groups) was approved by the National Health Service Research Ethics Committee in October 2013 (12/NW/0713). Recruitment opened in January 2013 and was completed in July 2013. Healthy volunteer samples were taken from the EHPC dose-ranging and reproducibility trial, approved by the same Research Ethics Committee in October 2011 (11/NW/0592). Recruitment for this study ran from October 2011 until December 2012. LRTI trial: (NCT01861184), EHPC dose-ranging and reproducibility trial: (ISRCTN85403723). Keywords: IgM antibodies, Pneumococcus, Vaccines, Immune senescence, Proteins Background . Eighty per cent of CAP occurs in people ≥60 years Community-acquired pneumonia (CAP) has an inci- [5–7], and this has been attributed to immune senescence, dence of 5–11 per 1000 adult population [1, 2], with an impairment of protective airway reflexes , reduced airway associated mortality between 5 and 20%, increasing to mucociliary clearance [9, 10] and alterations in respiratory 50% in cases admitted to the intensive care unit . The tract immune function [11, 12]. Polysaccharide-based vac- most common cause of CAP is Streptococcus pneumoniae cines are recommended for older adults: the pneumococcal conjugate vaccine (PCV) is now licensed for adults over the age of 50 in the United States (US) and the pneumococcal polysaccharide vaccine (PPV) is recommended to people * Correspondence: email@example.com over 65 years of age in the United Kingdom (UK). However, Esther L. German and Bahij Al-Hakim contributed equally to this work. Respiratory Infection Group, Liverpool School of Tropical Medicine, the true levels of protection conferred by these vaccines in Liverpool, UK older adults are unclear [13–16]. They also have significant Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. German et al. Pneumonia (2018) 10:5 Page 2 of 7 short-comings with regards to limited pneumococcal sero- their primary end-points reported elsewhere: the LRTI type coverage. Protein-based vaccines are being investigated trial  and the dose-ranging trial . The volunteers as alternative immunization strategies, on the basis that can be separated into three cohorts: LRTI, control (both they could provide full serotype coverage by targeting con- from the LRTI trial) and healthy (taken from the served proteins. As immunogenicity in vivo will depend on dose-ranging trial). exposure to the host immune system, surface-expressed The LRTI cohort consisted of patients with a diagnosis proteins are obvious potential vaccine candidates. of LRTI, based on presentation with symptoms of re- The protective role of antibody responses to pneumo- spiratory infection with ≥2 of the following clinical signs: coccal infection is well described. IgM antibodies are the “cough, breathlessness, pleuritic chest pain, fever and first class of antibodies to be produced in a primary re- increased or new sputum production” . Without sponse to microbial challenge. Although they bind with additional radiological consolidation, LRTI patients can- low affinity they exhibit a broad specificity to a variety of not be considered to have CAP, but this broader cohort antigens . Murine models have demonstrated that was chosen because of its clinical relevance in the UK the passive transfer of IgM antibodies targeting pneumo- hospitals setting . coccal polysaccharides can improve survival following a The control cohort comprised patients admitted to lethal pneumococcal challenge, suggesting that IgM anti- hospital for reasons other than LRTI. They had no re- body may be sufficient to confer protection against spiratory symptoms, and were age- and gender-matched pneumococcal disease . The therapeutic potential of to the LRTI patients. an immunoglobulin preparation enriched with IgM for The healthy cohort was formed of healthy volunteers the treatment of severe CAP is under investigation . aged 18–60 with no concurrent co-morbidities. Levels of antibodies to pneumococcal polysaccharides decline with aging, with IgM levels being more affected Sample collection than the IgG subclass [20–22]. Levels of IgG to several Nasal washes and serum samples were taken from LRTI pneumococcal protein antigens are also reduced in the and control group volunteers within 3 days of hospital elderly . admission. Baseline nasal washes and serum samples Pneumococcal surface protein A (PspA) is a major and were taken from healthy volunteers by appointment. well characterized virulence factor of the pneumococcus. Nasal washes were processed as described previously Antibodies directed against PspA augment C3 depos- [27, 28] and used to determine pneumococcal carriage ition, and immunization with PspA confers protection to status and density by classical microbiology and by lytA a variety of murine infection models [23, 24]. PspA is qPCR. Urine from LRTI and control volunteers was col- expressed in the majority of clinically important lected to perform the BinaxNOW (Alere International pneumococcal serotypes  and clade 4 in particular Ltd., Ireland) (urine chromatography) test. exhibits broad cross reactivity , allowing for sensitive detection of anti-PspA antibodies. Bacterial strains Despite evidence that IgM antibodies may play a role An unencapsulated D39 strain with deleted cpsD in anti-pneumococcal defence, and that IgG antibodies (D39-DΔ) (donated by Professor Jeremy S. Brown, to pneumococcal proteins have protective potential, the University College, London) was cultured in impact of age on levels of IgM antibodies to pneumo- Todd-Hewitt broth with 0.5% yeast extract (THY) until coccal proteins in humans has not been investigated. the mid-log phase. Bacteria was then pelleted, washed in This study seeks to address this knowledge gap by inves- phosphate buffered saline (PBS) and either used for tigating changes in levels and function of IgM antibodies whole cell ELISA (WCE) or resuspended in THY+ 20% against pneumococcal proteins in relation to aging and glycerol and stored at − 80 °C for later use in an im- lower respiratory tract infection (LRTI) using the PspA munoglobulin binding assay. clade 4 (PspA4) and an unencapsulated pneumococcal strain. It was hypothesised that as subjects age, levels and binding capacity of IgM antibodies against pneumo- Enzyme-linked immunosorbent assay (ELISA) coccal proteins in serum would be impaired and that pa- ELISA was used to quantify levels of IgM antibodies in tients hospitalized with LRTI would have lower IgM the serum samples as previously described . Briefly, levels and functionality when compared to controls. 96-well plates (Nunc, Denmark) were coated with car- bonate/bicarbonate buffer containing capture antigens/ Methods antibodies. The capture antigens/antibodies included Study subjects 1 μg/ml recombinant PspA4 (kindly donated by Dr. Serum samples used in this study were collected as part Eliane Miyaji, Butantan Institute, Sao Paulo, Brazil), the of two clinical trials, both of which have already had non-encapsulated D39-DΔ pneumococcal strain and German et al. Pneumonia (2018) 10:5 Page 3 of 7 anti-human IgM μ chain-specific antibody (I2386, deposition multiplied by the geometric mean fluorescence Sigma-Aldrich, St Louis, Missouri, USA). of the bacterial population positive for IgM. Plates were washed then blocked with 1% bovine serum albumin(BSA)-PBS before adding serial dilutions Statistical analysis of serum samples. Standard curves for calculating total Linear regression analysis was used to correlate levels IgM were made using purified total IgM from serum of antibodies with age. Antibody levels were log (I8260, Sigma-Aldrich, USA) at a level of 1 mg/ml. WCE transformed to obtain normal distribution then ana- and anti-PspA4 values were based on a standard pool lysed by one-way ANOVA with the Bonferroni correc- serum with an IgM level of 4000 arbitrary units/μl (do- tion to compare levels between the three groups. nated by Prof David Briles, University of Alabama). Analyses were performed using GraphPad Prism v5 IgM was bound to a goat anti-human IgM polyclonal (GraphPad Inc., California, USA) and significance was antibody conjugated to biotin (Abcam, Cambridge, UK). set at p <0.05. The conjugate was quantified by streptavidin-alkaline phosphatase (Bio-Rad Laboratories, Hemel Hempstead, Results UK) using 4-Nitrophenyl phosphate disodium salt hexa- Clinical trials hydrate (N9389, Sigma-Aldrich, USA) as the substrate Overall, 38 hospital inpatients were enrolled in the for development. Absorbance at 405 nm wavelength was LRTI trial, equally divided between patients with a determined using the Fluostar Omega® (BMG Labtech, diagnosis of LRTI (n = 19) and controls (n = 19). All Ortenberg, Germany) plate reader. A standard curve was LRTI patients, and 3 control patients, had been fitted using a 4-parameter fit model. treated with antibiotics before recruitment to this study . However, none of the control patients pre- sented with a symptomatic infection. 10 volunteers Flow cytometry were chosen from the dose-ranging study to be in- Immunoglobulin deposition on whole live unencapsulated cluded in this analysis as healthy volunteers. pneumococci was assayed using a modification of a pub- Table 1 outlines cohort characteristics. The mean lished flow cytometry assay . Briefly, D39-DΔ resus- age for LRTI patients was 64.5 years ±15.8 and pended in THY + 20% glycerol was grown to mid-log 64.6 years ±14.5 for the control group. The mean phase in THY media with erythromycin, before two cycles age of the healthy group was 21.2 years ±2.4. A of washing with PBS. Serum from patient groups was similar percentage of volunteers were female in all pooled and diluted in PBS at ratios of 1:2 and 1:20. Fixed three cohorts: 53% for LRTI and control groups, and volumes of the bacterial suspension were washed and re- 50% for healthy volunteers. Risk factors for pneumo- suspended in 100 μl of pooled serum before incubation coccal infection were recorded for both LRTI and for 30 min at 37 °C. Samples were pelleted, resuspended control cohorts. Vaccination with PPV and contact in IgM-PE-Cy5 (Clone G20–127, BD Biosciences, Franklin with children was similar between both groups, Lake, NJ, USA) and incubated for 20 min at 37 °C. Bac- whereas LRTI patients were more likely to be teria were washed and the level of IgM binding measured smokers, use corticosteroids and have COPD and/or by flow cytometry using a BD LSR II (BD Biosciences, asthma (Table 1). New Jersey, USA). The level of binding was calculated as Evidence was found of recent pneumococcal exposure the percentage of the bacterial population positive for IgM in 50% (19/38) of the study’s patients, either by detection Table 1 Study population characteristics LRTI (n = 19) Controls (n = 19) Healthy volunteers (n = 10) Age (mean ± SD) (yr) 64.5 (15.8) 64.6 (14.5) 21.2 (2.4) 10 (53) 10 (53) 5 (50) Female gender (n [%]) Smoker/ex-smoker (n [%]) 15 (79) 10 (53) 0 (0) PPV (n [%]) 7 (37) 8 (42) 0 (0) Contact with children (n [%]) 10 (53) 12 (63) 0 (0) Corticosteroid use (n [%]) 16 (84) 3 (16) 0 (0) COPD (n [%]) 8 (42) 2 (11) 0 (0) Asthmatic (n [%]) 5 (26) 1 (5) 0 (0) COPD, chronic obstructive pulmonary disease; LRTI, lower respiratory tract infection; PPV, pneumococcal polysaccharide vaccine German et al. Pneumonia (2018) 10:5 Page 4 of 7 of pneumococcal nasal carriage or BinaxNOW (urine Effect of age on immunoglobulin M antibody levels in immunochromatography) test . Of these, 11 serum belonged to the LRTI cohort. There was no significant While the total levels of IgM trended to increase with in- difference in IgM antibody levels between pneumococcal crease of age (r =0.15, p =0.006) (Fig. 1a), no correlation carriers and non-carriers, nor was there any correlation was observed for levels of specific pneumococcal IgM between IgM antibody levels and carriage density by qPCR (data not shown). Fig. 2 Levels of IgM in relation to LRTI. The level of total IgM was Fig. 1 Levels of IgM in relation to age. Levels of (a) total IgM, (b) examined for patients with LRTI, hospital Controls and a young IgM to the unencapsulated D39-ΔD pneumococcus and to the (c) cohort of Healthy volunteers. Levels of (a) total IgM, (b) IgM to the Pneumococcal Surface Protein A (PspA4) were plotted against unencapsulated D39-ΔD pneumococcus and to the (c) volunteer age. Correlations were analysed using linear Pneumococcal Surface Protein A (PspA4) are shown. Mean values ± regression analysis SD are shown. * p < 0.05 using ANOVA with Bonferroni’s correction German et al. Pneumonia (2018) 10:5 Page 5 of 7 antibody and age: D39-DΔ (r =0.07, p = 0.05) and PspA4 and healthy groups) (Fig. 2a). No significant difference was (r =0.005, p =0.60) (Figs. 1b and c). observed in IgM antibody levels to D39-DΔ (p =0.64 for ANOVA analysis) or to PspA4 (p =0.14 for ANOVA ana- Effect of lower respiratory tract infection on lysis) between any of the groups (Figs. 2b and c). immunoglobulin M levels There was no difference in total IgM levels between LRTI Immunoglobulin binding to whole-cell unencapsulated and control groups. The LRTI group had higher levels of pneumococcus total IgM when compared to the healthy group (p =0.01 for The immunoglobulin binding assay was performed to ANOVA analysis, p < 0.05 for the difference between LRTI assess changes in the binding capacity of IgM with aging Fig. 3 Flow cytometric assessment of IgM binding to pneumococcus surface. Pooled sera from different volunteer groups were added to bacteria. Two experiments using different dilutions (1:2 and 1:20) of sera were performed. a Histogram of surface binding of IgM to intact pneumococcus D39-DΔ. b Surface binding of IgM from pooled serum samples expressed as the percentage of the bacterial population positive for IgM deposition multiplied by the geometric mean fluorescence of the bacterial population positive for IgM German et al. Pneumonia (2018) 10:5 Page 6 of 7 and LRTI status. Sera from ≥60 control group showed impact on antibody levels measured by whole cell no decrease in binding compared to younger volunteers ELISA, differences were observed in antibody binding as from the healthy group (Figs. 3a and b). Contrary to the assessed by flow cytometry. This discrepancy could be study’s initial hypothesis, the ≥60 LRTI group exhibited explained by bacterial rupture. the highest level of IgM binding while the < 60 control Limitations of this study include the small number of group showed the lowest levels of binding. samples and the unknown etiology of LRTI of these pa- tients. This study cohort also had significant heterogen- Discussion eity with respect to many factors affecting These results demonstrate that the levels and binding immunoglobulin levels; for example, vaccination status, capacity of IgM to pneumococcal proteins are unaltered co-morbidities, corticosteroid treatment, and history of with aging. Patients with LRTI did not show decreased previous pneumococcal infection . Furthermore, 12 IgM antibody to D39-DΔ or PspA4 compared to either of the LRTI patients received Clarithromycin prior to re- the control or healthy groups. The study observed cruitment. The activities of 14-membered macrolide an- higher IgM binding to pneumococcus in a flow cytome- tibiotics are known to exert immunomodulatory effects try assay for sera from LRTI patients over 60 years.  and this may have affected IgM responses to High levels of total IgM in patients with LRTI cannot S.pneumoniae in this cohort. be an artefact of current infection, but rather of aging, because control patients without infection presented Conclusions with similar total IgM levels, but the healthy group had In summary, these findings suggest that IgM antibodies significantly lower total IgM levels. Although only IgM against pneumococcal proteins do not decrease with age antibodies against pneumococcal polysaccharides and and this warrants further investigation into IgM anti- proteins can be expected to confer protection against bodies against pneumococcal proteins and its role in im- pneumococcal infection, it is nevertheless interesting to munity through pneumococcal protein vaccination. note that total IgM antibody levels are maintained des- Abbreviations pite immune senescence. CAP: Community Acquired Pneumonia; D39-DΔ: Unencapsulated D39 strain A study of IgM levels in mice found that total IgM with deleted cpsD; LRTI: Lower Respiratory Tract Infection; PBS: Phosphate Buffered Saline; PCV: Pneumococcal Conjugate Vaccine; PPV: Pneumococcal levels were increased in older animals . However, the Polysaccharide Vaccine; PspA: Pneumococcal surface protein A; THY: Todd- authors found that anti-pneumococcal protein IgM anti- Hewitt broth with 0.5% yeast extract; WCE: Whole Cell ELISA body levels (as indicated by antibodies to phosphoryl Acknowledgements choline, a pneumococcal cell wall antigen) dropped with The authors are grateful to Professor Jeremy S Brown (University College, age. This discrepancy with the present study’s data could London, UK), Dr. Eliane N Miyaji (Butantan Institutue, Sao Paulo, Brazil) and be explained by the different choice of antigen or the Professor David Briles (University of Alabama, Alabama, USA), for their generous contributions of D39-DΔ (JSB), recombinant PspA4 (ENM) and limitation of animal models (which are immunologically standard serum (DB). They also appreciate the helpful comments and advice naïve) to represent human responses (which are fre- provided by Dr. Jamie Rylance, Dr. Hugh Adler and Dr. Jesús Reiné (Liverpool quently re-challenged by in vivo exposure to pneumo- School of Tropical Medicine, Liverpool, UK) upon review of the manuscript. coccus through nasal carriage) . IgM from older Funding mice (18- or 24-month) was less protective against This work was financed by The Bill & Melinda Gates Foundation Grand pneumococcal challenge when compared to younger Challenge Exploration programme, Medical Research Council/Sao Paulo Research Foundation bilateral agreement (MRC-FAPESP) and the Wellcome mice (3-month) . The present study showed, how- Trust. The researchers work entirely independently from the funders. ever, that IgM in adults over the age of 60 retains the ability to bind to non-encapsulated S. pneumoniae. Availability of data and materials The datasets used and/or analysed during the current study are available In whole-cell ELISA, in addition to surface protein an- from the corresponding author on reasonable request. tigens, cell wall antigens are also present, to which IgM binding may occur; however, whether these antibodies Authors’ contributions confer meaningful protection has been questioned [33, The LRTI study was designed by AMC, ADHW, and SBG. Samples were collected by ADHW and processed by JFG and AB. The experiments were 34]. It has been suggested that bacterial autolysis during designed by BAH, DMF and SBG. Laboratory work was carried out by BAH the overnight coating step releases internal antigens and ELG with the assistance of AB, SHP (flow cytometry), JFG, and EM which would not in vivo be presented to the immune (ELISAs). Data was analysed and interpreted by BAH, SBG, DMF, EM and ELG. The manuscript was prepared for submission by BAH, ELG, SHP and DMF. system . Antibodies to these internal and cell wall The final version of the manuscript was approved by all authors prior to antigens could conceivably lead to an overestimation of submission. levels of IgM antibody against surface protein antigens. Ethics approval and consent to participate To address this issue, the study also used a flow cyto- The samples used for these experiments were taken from volunteers metric approach to evaluate antibody binding to intact participating in studies approved by the North West-Liverpool East Research pneumococcus. Whereas cohort and age showed no Ethics Committee (12/NW/0713 for LRTI and Control groups; 11/NW/0592 for German et al. Pneumonia (2018) 10:5 Page 7 of 7 the Healthy group). All studies were conducted in compliance with the 18. Baxendale HE, Johnson M, Stephens RCM, Yuste J, Klein N, Brown JS, Declaration of Helsinki and informed consent was gained prior to all Goldblatt D. 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Published: Jun 5, 2018