Humoral immune response to SARS-CoV-2 mRNA vaccines is associated with choice of vaccine and systemic adverse reactions.

Purpose: Although the fast development of safe and effective messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 has been a success, waning humoral immunity has led to the recommendation of booster immunization. However, knowledge of the humoral immune response to different booster strategies and the association with adverse reactions is limited. Materials and Methods: We investigated adverse reactions and anti-spike protein immunoglobulin G (IgG) concentrations among health care workers who received primary immunization with mRNA-1273 and booster immunization with mRNA-1273 or BNT162b2. Results: Adverse reactions were reported by 85.1% after the first dose, 94.7% after the second dose, 87.5% after a third dose of BNT162b2, and 86.0% after a third dose of mRNA-1273. They lasted for a median of 1.8, 2.0, 2.5, and 1.8 days, respectively; 6.4%, 43.6%, and 21.0% of the participants were unable to work after the first, second, and third vaccination, respectively, which should be considered when scheduling vaccinations among essential workers. Booster immunization induced a 13.75-fold (interquartile range, 9.30-24.47) increase of anti-spike protein IgG concentrations with significantly higher concentrations after homologous compared to heterologous vaccination. We found an association between fever, chills, and arthralgia after the second vaccination and anti-spike protein IgG concentrations indicating a linkage between adverse reactions, inflammation, and humoral immune response. Conclusion: Further investigations should focus on the possible advantages of homologous and heterologous booster vaccinations and their capability of stimulating memory B-cells. Additionally, understanding inflammatory processes induced by mRNA vaccines might help to improve reactogenicity while maintaining immunogenicity and efficacy.

Large inter-individual variability of cellular and humoral immunological responses to mRNA-1273 (Moderna) vaccination against SARS-CoV-2 in health care workers.

PURPOSE: Studies on the immune responses to severe acute respiratory syndrome coronavirus 2 vaccines are necessary to evaluate the ongoing vaccination programs by correlating serological response data and clinical effectiveness data. We performed a longitudinal immunological profiling of health care workers vaccinated with mRNA-1273 (Moderna, Cambridge, MA, USA). Half of these vaccinees had experienced a mild coronavirus disease 2019 (COVID-19) infection in the spring of 2020 ("COVID-recovered" cohort), whereas the other half of the vaccinees had no previous COVID-19 infection ("COVID-naive" cohort). MATERIALS AND METHODS: Serum was drawn at multiple time points and subjected to assays measuring anti-Spike immunoglobulin G (IgG), avidity of anti-Spike IgG, avidity of anti-receptor binding domain (RBD) IgG, virus neutralizing activity, and interferon-γ release from stimulated lymphocytes. RESULTS: Between both cohorts and within each cohort, we found remarkable inter-individual differences regarding cellular and humoral immune responses to the Moderna mRNA-1273 vaccine. CONCLUSION: First, our study indicates that the success of mRNA-1273 vaccinations should be verified by serological assays in order to identify "low-responders" to vaccination. Second, the kinetics of anti-S IgG and neutralizing activity correlate well with clinical effectiveness data, thus explaining incipient protection against infection 2 weeks after the first dose of mRNA-1273 in COVID-naive vaccinees. Third, our IgG-avidity data indicate that this incipient protection is mediated by low-avidity anti-RBD IgG and low-avidity anti-S IgG.

Severity of adverse reactions is associated with T-cell response in mRNA-1273 vaccinated health care workers.

Knowledge about mRNA-1273 elicited T-cell response is limited. We investigated adverse reactions and interferon gamma release by specific T-cells among mRNA-1273 vaccinated health care workers. Seven to 13 weeks after complete vaccination low levels of specific T-cells were detected not correlating with antibody response. Severity of symptoms after first and number of symptoms after second immunization were associated with T-cell response. Assessment of T-cell response in addition to antibody response is crucial because even few specific T-cells could add to protection against infection. Investigation of mRNA-1273 induced inflammatory processes might help improve reactogenicity and immunogenicity.

Two novel SARS-CoV-2 surrogate virus neutralization assays are suitable for assessing successful immunization with mRNA-1273.

BACKGROUND: Due to large vaccination efforts with novel vaccines there is an increasing need for laboratory tests assessing successful immunizations with SARS-CoV-2 vaccines. Unfortunately classical neutralization assays are laborious, time-consuming and require an adequate biosafety level laboratory. Recently, convenient ELISA-based surrogate neutralization assays (sVNTs) for determination of neutralizing SARS-CoV-2 antibodies have been developed. STUDY DESIGN: Our study compares the two novel ELISA-based SARS-CoV-2 surrogate neutralization assays "cPass SARS-CoV-2 Surrogate Virus Neutralization Test Kit" (GenScript Biotech, USA) and the "TECO SARS-CoV-2 Neutralization Antibody Assay" (TECOmedical, Switzerland) using 93 sera drawn from health care workers (HCVs) 2-3 weeks following the second vaccination with mRNA-1273 and 40 control sera from the pre-SARS-CoV-2 era before 2019. RESULTS: We found a sensitivity of 100% and 91,4% and a specificity of 100% and 100% for the GenScript assay and the TECO assay, respectively. Both sVNTs show a high correlation with anti-S IgG. Moreover, both sVNTs correlate well with each other. CONCLUSIONS: Surrogate neutralization assays based on the RBD as bait feature a high specificity and sensitivity for identifying humoral neutralizing activity in individuals vaccinated with the spike-based vaccine mRNA-1273. Although these assays appear well-suited for confirming successful vaccinations with spike-based vaccines, additional studies should compare both assays regarding other purposes such as screening COVID-recovered patients or individuals vaccinated with inactivated whole virus vaccines.

Nasopharyngeal Carriage in Children After the Introduction of Generalized Infant Pneumococcal Conjugate Vaccine Immunization in Germany.

Epidemiological data on nasopharyngeal (NP) bacterial carriage in children in Germany are scarce. We prospectively characterized NP colonization to evaluate the impact of pneumococcal immunization. We longitudinally collected NP swabs from 2-month-old infants (visit 1; V1) at eight representative pediatric offices 10/2008-06/2009. The second swabs were taken at age 9-12 months (V2); the third swab was taken 3-6 months after the booster vaccination at age 17-19 months (V3), and the fourth swab (V4) at age 59-61 months. Samples were broth enriched, cultured for bacteria, and isolates were serotyped. Demographic risk factors for colonization were evaluated. Among 242 vaccinees, bacterial NP carriage increased with age [from 27.2% (V1) to 70.1% (V4)]; leading isolates were S. pneumoniae, H. influenzae, M. catarrhalis, and S. pyogenes. Overall pneumococcal carriage increased [14.7% (V1), 31.5% (V2), 34.8% (V3), 42.2% (V4)], being even greater among day-care attendees. Serotype distribution changed during the study period, with vaccine serotypes declining. At visit 4, 10-valent pneumococcal conjugate vaccine (PCV10) serotypes were no longer among the NP flora, while some serotypes unique to 13-valent pneumococcal conjugate vaccine (PCV13; 3 and 19A) were found. In Germany, universal infant PCV immunization was associated with an almost complete eradication of PCV-serotypes and concomitant increase of non-PCV-serotypes, mainly 11A, 22F, and 23A.

Evaluation of the QuantiFERON SARS-CoV-2 interferon-É£ release assay in mRNA-1273 vaccinated health care workers.

Current studies focus on cellular and humoral immunity induced by novel SARS-CoV-2 vaccines. Non-responders to vaccinations are not uncommonly encountered in clinical medicine (e.g. in the field of hepatitis B). Whereas vaccine-induced humoral immunity against SARS-CoV-2 is compromised by emerging Variants of Concern (VOCs), cellular immunity against SARS-CoV-2 is emerging as resilient against VOCs. Thus commercially available test kits for diagnostic laboratories designed to evaluate cellular immune responses to SARS-CoV-2 are urgently needed. Here we evaluated the novel QuantiFERON SARS-CoV-2 assay (Qiagen) measuring INF-É£ release induced by two spike-derived peptide pools (Ag1 and Ag2) in a cohort of health care workers vaccinated with the mRNA-1273 vaccine and confirmed humoral response. Our study indicates the usefulness of this novel assay for routine laboratories to evaluate cellular immunity against SARS-CoV-2 in response to mRNA-1273 vaccination.

Bacterial Spectrum of Spontaneously Ruptured Otitis Media in a 7-Year, Longitudinal, Multicenter, Epidemiological Cross-Sectional Study in Germany.

We analyzed middle ear fluid (MEF) and nasopharyngeal swabs (NPS) from spontaneously ruptured acute otitis media (AOM) cases occurring in children under 5 years in Germany. The aim of the study was the assessment of disease burden and bacterial etiology in the era of routine pneumococcal vaccination. Furthermore, we aimed to compare isolates from MEF with isolates from NPS and to analyze the Streptococcus pneumoniae serotype distribution. We analyzed MEF and NPS samples in children 2 months to 5 years for vaccination status, frequency of bacterial strains, serotype/emm-type distribution of S. pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes; and intraindividual correlation between MEF and NPS. From 2008 to 2014, MEF samples were collected from 2,138 subjects of which 2,001 (93.6%) also provided an NPS sample. In 851 of 2,138 MEF samples (39.8%), we identified organisms with confirmed pathogenic potential-S. pyogenes: 315 (14.7%), S. pneumoniae: 170 (8.0%), Staphylococcus aureus: 168 (7.9%), H. influenzae: 133 (6.2%), and Moraxella catarrhalis. Among NPS samples, 1,018 (50.9%) contained S. pneumoniae, 775 (38.7%) H. influenzae, 648 (32.4%) M. catarrhalis, and 344 (17.2%) S. pyogenes. Over the seven study years, the number of AOM patients steadily decreased, while the recruiting base remained constant. S. pneumoniae MEF isolates decreased by 86%, with serotype 3 being the most prevalent (25.7-42.9%). PCV13-non-PCV7-non-3 serotypes reduced to 0%. Among NPS, PCV7 serotypes decreased from 14.1 to 3.7%, PCV10: 17.6 to 3.7%, and PCV13: 55.3 to 25.7%. PCV13-non-PCV7-non-3 serotypes increased in the first 3 years of the study (17.1-22.9%), then decreased to 4.6% in year 7. Non-typeable H. influenzae reduced from 87.1 to 41.7% in MEF and from 91.4 to 54.2% in NPS. MEF and NPS isolates from the same subject were identical for 91.9% of S. pneumoniae, 99.0% of S. pyogenes, and 83.3% of H. influenzae. Among PCV7-vaccinated children, 5.6% had a PCV7 vaccine type in the MEF sample, and among PCV13-vaccinated children, 51.7% had a PCV13 serotype. Among non-vaccinated children, the percentages were 14.8 and 70.4. Pneumococcal conjugate vaccination has impacted the prevalence and etiology of spontaneously ruptured otitis media among children in Germany. Overall case numbers and pneumococcal vaccine type cases have strongly decreased.

Comparison of the SARS-CoV-2 Rapid antigen test to the real star Sars-CoV-2 RT PCR kit.

There is an ongoing need for reliable antigen assays for timely and easy detection of individuals with acute SARS-CoV-2 infection. Using 75 swabs from patients previously tested positive by SARS-CoV-2 PCR and 75 swabs from patients previously tested negative by SARS-CoV-2 PCR, we investigated the sensitivity and specificity of the SARS-CoV-2 Rapid Antigen Test (Roche). We determined a specificity of 96 %. The assay's sensitivity with samples with a cycle threshold of < 25, 25 - <30, 30 - <35, and> = 35 was 100 %, 95 %, 44.8 % and 22.2 %, respectively. We conclude that sensitivity and specificity of the antigen assay is inferior to the PCR assay. However, the antigen assay may be a quick and easy to perform alternative for differentiation of individuals contagious for SARS-CoV-2 from non-contagious individuals.

Determination of SARS-CoV-2 antibodies with assays from Diasorin, Roche and IDvet.

There is an ongoing need for highly reliable serological assays to detect individuals with past SARS-CoV-2 infection. Using 75 sera from patients tested positive or negative by SARS-CoV-2 PCR, we investigated the sensitivity and specificity of the Liaison SARS-CoV-2 S1/S2 IgG assay (DiaSorin), the Elecsys Anti-SARS-CoV-2 assay (Roche), and the ID Screen SARS-CoV-2-N IgG indirect kit (IDVet). We determined a sensitivity of 95.5 %, 95.5 %, and 100 % and a specificity of 90.5 %, 96.2 %, and 92.5 % for the DiaSorin assay, the Roche assay, and the IDVet assay, respectively. We conclude that serologic assays combining very high sensitivity and specificity are still not commercially available for SARS-CoV-2. For maximizing sensitivity and specificity of SARS-CoV-2 serological diagnostics, the combination of two assays may be helpful.

Comparison of four new commercial serologic assays for determination of SARS-CoV-2 IgG.

BACKGROUND: Facing the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for serological assays identifying individuals with past coronavirus disease 2019 (COVID-19). STUDY DESIGN: Our study is the first to compare four new commercially available assays using 75 sera from patients tested positive or negative by SARS-CoV-2 PCR: the anti SARS-CoV-2 ELISA (IgG) (Euroimmun, Germany), the EDI New Coronavirus COVID-19 IgG ELISA, (Epitope diagnostics (EDI), USA), the recomWell SARS-CoV-2 IgG ELISA (Mikrogen, Germany), and the SARS-CoV-2 Virachip IgG (Viramed, Germany). RESULTS: We found a sensitivity of 86.4 %, 100 %, 86.4 %, and 77.3 % and a specificity of 96,2 %, 88,7 %, 100 %, and 100 % for the Euroimmun assay, the EDI assay, the Mikrogen assay, and the Viramed assay, respectively. CONCLUSIONS: Commercially available SARS-CoV-2 IgG assays have a sufficient specificity and sensitivity for identifying individuals with past SARS-CoV-2 infection.

Correction: Limited indirect effects of an infant pneumococcal vaccination program in an aging population.

[This corrects the article DOI: 10.1371/journal.pone.0220453.].

Reference change values of M-protein, free light chain and immunoglobulins in monoclonal gammopathy.

OBJECTIVES: Clinical decisions in patients with monoclonal gammopathies may be highly imprecise because of variations of parameters used in diagnosis. In this study, we aimed to calculate the variation in M-protein, free light chains (FLCs), and immunoglobulins in respective patients. DESIGN & METHODS: We analyzed the data of clinically stable patients with monoclonal gammopathy (MG), which were monitored for 7-years to determine the biological variations and reference change values (RCV) of serum M-protein, monoclonal serum FLCs and immunoglobulin (Ig) concentrations. Patients that were included in the study had no change in diagnosis and showed <5 g/L change in serum M-protein during the monitoring. From the patients included at least 3 consecutive samples were analyzed within 8 months and 7 years of initial diagnosis. RESULTS: The total coefficient of variations (CV) was calculated for M-protein and involved/uninvolved fractions of FLCs and immunoglobulins. From 38 patients and 456 samples that were included in the study, the total CVs were calculated for serial M-proteins (8.9%), serum involved FLCs (iFLC, 21.4%), involved Ig (i-Ig, 8.7%) and uninvolved Ig (u-Ig, 9.1%). Combining these CVs and the interassay analytical CVs, we calculated the biological CV for the serum M-protein (8.4%), serum iFLC concentration (21.1%), i-Ig (8.6%) and u-Ig (9.0%). A significant correlation was found in multiple myeloma patients between the κ/λ light chain ratio (rFLC) with i-Ig, the difference between i-Ig level and u-Ig level (d-Ig) and ratio Ig (r-Ig) (r = 0.790, 0.703 and 0.711, respectively). These correlations were not found in patients suffering from MG of undetermined significance and smoldering multiple myeloma. CONCLUSIONS: i-Ig determinations may be an alternative to M-protein for MGs. The variations in serum FLC measurements during MG monitoring were greater than those observed in serum M-proteins and therefore need to be more rigorously revised for recommendations.

Limited indirect effects of an infant pneumococcal vaccination program in an aging population.

BACKGROUND: A general recommendation for adult pneumococcal vaccination with 23-valent polysaccharide vaccine (PPV23) for adults 60 and older has been in place in Germany since 1998, but uptake has been low. Just over a decade after the implementation of an infant pneumococcal conjugate vaccine recommendation, we examined indirect protection effects on adult invasive pneumococcal disease (IPD) in Germany. METHODS AND FINDINGS: Reported IPD cases decreased in children under two years of age from 11.09 per 100,000 in 2003-2006 to 5.94 per 100,000 in 2017/18, while in adult age groups, reported IPD cases rose across the board, most dramatically in adults 60 years of age and over, from 1.64 to 10.08 cases per 100,000. PCV13-type IPD represents 31% of all cases in this age group, the lion's share of which is due to the rapid increase of serotype 3 IPD, which, by itself, has reached 2.11 reported cases per 100,000 and makes up 21% of all IPD cases in this age group. The two vaccine formulations currently in development (PCV15 and PCV20) would increase current (PCV13) coverage by 8.5% points and 28.0% points in children, while in adults coverage would increase by 10.4% points and 21.9% points, respectively. CONCLUSIONS: While original models predicted that indirect effects of childhood vaccination would suffice for adults, it seems that the herd protection effect has reached its limit, with vaccine serotypes 4, 19F, and 19A IPD persisting in adults after initial reductions, and serotype 3 IPD not showing any herd protection effect at all.

Regional variations in serotype distribution and vaccination status in children under six years of age with invasive pneumococcal disease in Germany.

OVERVIEW: The protective effect of infant pneumococcal conjugate vaccine (PCV) recommendation can be seen in Germany as a whole and in smaller regional groups. Comparisons between population-normalized geographic regions of Germany show different serotype distributions after program implementation, particularly in non-vaccine serotypes. The prior distinct differences in serotype distribution in children between the former East and former West German federal states have vanished. Children under six remain a vulnerable group, but the occurrence of vaccine-type (VT) invasive pneumococcal disease (IPD) in children correctly vaccinated (using a three-dose primary series plus one booster dose) with PCV13 was low (9 out of 374 cases, 2.4%). However, only 18.4% of children in Germany with IPD were correctly vaccinated with PCV13 according to the recommended schedule. Continued surveillance and better schedule adherence are essential to definitively establish the most effective PCV administration schedule. VACCINATION EFFECTS: For all PCV products used in Germany (PCV7, PCV10, and PCV13), vaccination status was the most common statistically significant predictor of infection with a particular serotype: Unvaccinated children old enough to have received at least one dose of vaccine in the PCV7 group had significantly higher odds (OR: 6.84, 95%CI: 2.66-22.06, adjusted for per capita income and residence in the northeastern federal states) of contracting VT IPD. In the PCV10 group, VT IPD had an OR of 4.52 (95% CI: 1.60-15.62, adjusted for year of infection, median household size, and residence in the southern federal states) in unvaccinated children, and in the PCV13 group, unvaccinated children continued to have higher odds (OR: 6.21, 95%CI: 3.45-11.36, adjusted for year of infection, age of child, per capita income, residence in the southern federal states, and percentage of children using public daycare) of getting vaccine-type IPD. Being unvaccinated was the most frequent significant indicator for infection with vaccine-type serotypes for each analysis group, while geographic groupings showed more limited potential to predict serotype of infection in early childhood IPD in Germany.

Mining the Age-Dependent Reference Intervals of B Vitamins from Routine Laboratory Test Results.

OBJECTIVE: To describe the reference intervals of folate, vitamin B12, vitamin B6, and vitamin B1 by sex and age. METHODS: The study was performed by gathering data on 55,811 subjects from 57 medical centers. Groups were categorized based on age and grouped according to statistical significance values. The reference values for the different groups were determined using the Bhattacharya and Hoffmann methods. RESULTS: Vitamin B1 and B6 values and folate (vitamin B9) levels between the sexes were statistically significantly increased in the group aged 0 to 10 years. Likewise, we witnessed a similar increase in vitamin B12 levels in the group aged 0 to 5 years. However, low vitamin B6 levels (P <.001) were detected in nongeriatric patients (aged 0-60 years), and the reference intervals (3.4-41.9 µg/L) also were significantly different from those in the geriatric group (aged 61-100 years; 2.0-29.4 µg/L). CONCLUSION: A lower vitamin B6 reference limit allows detection of subclinical vitamin deficiency more precisely in the geriatric group; respective reference intervals should be revised accordingly.

Vitamin B1 interpretation: Erroneous higher levels in non-anemic populations.

OBJECTIVES: The aims of this study were to underline the interpretation of vitamin B1 and to evaluate whether differences in hemoglobin (Hb) levels and sex effect vitamin B1 results. METHODS: Simultaneously, whole blood vitamin B1 and complete blood count were determined in 2238 individuals. Groups were categorized on the basis of sex and Hb levels. Significance and correlation between groups and reference intervals of the study group were determined. RESULTS: There was an 8.4% (P < 0.001) difference between vitamin B1 levels of men and women, whereas the ratio of vitamin B1 to Hb showed a 0.12% (P = 0.921) difference. The reference interval for the ratio of vitamin B1 to Hb was 268 to 675 ng/g Hb. CONCLUSION: Vitamin B1 concentrations >48 µg/L should be interpreted with Hb levels to avoid postanalytical errors that mask deficiency. Therefore, in comparative studies, researchers need to pay attention to eliminate the effect of Hb on whole blood vitamin B1 levels.

Invasive Pneumococcal Disease in Refugee Children, Germany.

Refugee children in Germany are not routinely given a pneumococcal conjugate vaccine. Cases of invasive pneumococcal disease (IPD) in 21 refugee children were compared with those in 405 Germany-born children for 3 pneumococcal seasons. Refugee children had significantly higher odds of vaccine-type IPD and multidrug-resistant IPD than did Germany-born children.

Epidemiology and distribution of 10 superantigens among invasive Streptococcus pyogenes disease in Germany from 2009 to 2014.

A nationwide laboratory-based surveillance study of invasive S. pyogenes infections was conducted in Germany. Invasive isolates (n = 719) were obtained between 2009 and 2014. Most isolates were obtained from blood (92.1%). The proportions of isolates from cerebrospinal fluid, pleural fluid, synovial fluid and peritoneal fluid were 3.9%, 1.8%, 1.7% and 0.6%, respectively. The most common emm types were emm 1 (31.8%), emm 28 (15.4%) and emm 89 (14.5%). The most common superantigen genes (speA, speC, speG, speH, speI, speJ, speK, speL, speM, ssa) identified from S. pyogenes were speG (92.1%), speJ (50.9%), and speC (42.0%). Significant associations of superantigen genes with underlying conditions or risks were observed in speG, speH, speJ, and speK. Significant associations between emm types or superantigen genes with clinical complications were observed in emm type 3 and in superantigen gene speA 1-3. Most frequent clinical manifestations included sepsis 59.4%, STSS 6.3%, meningitis 5.4%, and necrotizing fasciitis 5.0% (significantly associated with emm1).

Fluoroquinolone resistance in Streptococcus pneumoniae isolates in Germany from 2004-2005 to 2014-2015.

Streptococcus pneumoniae is a major cause of bacterial pneumonia, sepsis and meningitis worldwide. Prevalence of levofloxacin-resistant S. pneumoniae isolates in Germany and associated mutations in the quinolone resistance determining regions (QRDRs), as well as serotype distribution and multi locus sequence types (MLST) are shown. 21,764 invasive S. pneumoniae isolates from Germany, isolated in the epidemiological seasons from 2004/05 to 2014/15 were analyzed at the German National Reference Centre for Streptococci (GNRCS) for their levofloxacin resistance by micro broth dilution method. All resistant (minimal inhibitory concentration (MIC) ≥8µg/ml) and intermediate (MIC >2µg/ml and <8µg/ml) isolates were selected for the present study. Additionally, 29 susceptible isolates were randomly selected. A total of ninety isolates were tested for their levofloxacin-MIC by Etest, their serotype and sequence type, as well as for point-mutations at the QRDRs in the genes parC, parE, gyrA and gyrB. Twenty-five isolates exhibited levofloxacin MICs <2µg/ml (Etest) and no mutations in the QRDRs. Four isolates with MICs=2µg/ml had one mutation in parC; isolates with MICs >2µg/ml all had one or more mutations in the QRDRs. Four of nine intermediate isolates had a mutation in either parC or gyrA, and four isolates had mutations in both parC and gyrB. One isolate had mutations in both parC and gyrA. All isolates with MICs ≥8µg/ml (52) had mutations in both topoisomerase IV and gyrase. Serotypes associated with levofloxacin resistance shifted from a majority of PCV13 serotypes before the introduction of the PCV13 vaccine towards non-PCV serotypes. Resistant isolates were almost exclusively found among adults (98.1%).

Effectiveness of Pneumococcal Conjugate Vaccines (PCV7 and PCV13) against Invasive Pneumococcal Disease among Children under Two Years of Age in Germany.

BACKGROUND: In this study we calculate the effectiveness of pneumococcal conjugate vaccines (PCV) against invasive pneumococcal disease (IPD) among children under the age of two years using the indirect cohort method. We also discuss the timeliness of vaccination and the residual cases of vaccine type IPD. METHODS AND FINDINGS: From July 2006 until June 2015, 921 IPD cases were reported and for 618 children (67.1%), the vaccination status at the time of infection could be accurately determined. Of these, 379 (61.3%) were vaccinated and 239 (38.7%) were not vaccinated. The adjusted vaccine effectiveness (VE) of PCV7 for all included serotypes + 6A was 80% (95% CI: 63-89) for at least one dose, 97% (89-100) after three primary doses (post primary) and 95% (57-100) post booster. The adjusted overall VE of PCV13 was 86% (74-93) for at least one dose, 85% (62-94) post primary and 91% (61-99) post booster. For the additional serotypes included in PCV13, the adjusted VE was 82% (66-91), 80% (46-93) and 90% (54-98) respectively. The serotype specific VE for at least one dose was high for serotypes 1 (83%; 15-97), 3 (74%; 2-93), 7F (84%; 18-98) and 19A (77%; 47-90). Only 39.5% of children with IPD obtained their first dose of PCV7 according to schedule (2nd dose: 32.9%, 3rd dose: 22.0%, booster dose: 63.6%). For children vaccinated with PCV13 values were slightly better: 43.8%, 33.5%, 26.3% and 74.3% respectively. Among 90 residual cases with PCV7 serotypes, 73 (81.1%) were in unvaccinated children, and 15 (16.7%) in children who had not obtained the number of doses recommended for their age, and only two (2.2%) in children vaccinated according to age. Of 82 cases with PCV13 serotypes occurring after the switch from PCV7 to PCV13, 56 (68.3%) were not vaccinated, 22 (26.8%) were incompletely vaccinated, and four (4.9%) were vaccinated according to age. CONCLUSIONS: Our data show a high effectiveness of pneumococcal conjugate vaccination in Germany. However, the administration of vaccine doses among children with IPD is often delayed, resulting in many vaccine type cases in non- or incompletely-vaccinated children. Whether the recently-implemented change to a 2+1 schedule will improve the timeliness of vaccination should be subject to careful monitoring.