Ten-valent Pneumococcal Conjugate Vaccine Research Articles

Long-term surveillance of invasive pneumococcal disease: The impact of 10-valent pneumococcal conjugate vaccine in the metropolitan region of Salvador, Brazil

BackgroundIn 2010, Brazil introduced the ten-valent pneumococcal conjugate vaccine (PCV10) in the national infant immunization program. Limited data on the long-term impact of PCV10 are available from lower-middle-income settings. We examined invasive pneumococcal disease (IPD) in Salvador, Bahia, over 11 years. MethodsProspective laboratory-based surveillance for IPD was carried out in 9 hospitals in the metropolitan region of Salvador from 2008 to 2018. IPD was defined as Streptococcus pneumoniae cultured from a normally sterile site. Serotype was determined by multiplex polymerase chain reaction and/or Quellung reaction. Incidence rates per 100,000 inhabitants were calculated for overall, vaccine-type, and non-vaccine-type IPD using census data as the denominator. Incidence rate ratios (IRRs) were calculated to compare rates during the early (2010–2012), intermediate (2013–2015), and late (2016–2018) post-PCV10 periods in comparison to the pre-PCV10 period (2008–2009). ResultsPre-PCV10, overall IPD incidence among all ages was 2.48/100,000. After PCV10 introduction, incidence initially increased (early post-PCV10 IRR 3.80, 95% CI 1.18–1.99) and then declined to 0.38/100,000 late post-PCV10 (IRR 0.15; 95% CI 0.09–0.26). The greatest reductions in the late post-PCV10 period were observed in children aged ≤2 years, with no cases (IRR not calculated) and those ≥60 years (IRR 0.11, 95% CI 0.03–0.48). Late post-PCV10, significant reductions were observed for both PCV10 serotypes (IRR 0.02; 95% CI 0.0–0.15) and non-PCV10 serotypes (IRR 0.27; 95%CI 0.14–0.53). Non-PCV10 serotypes 15B, 12F, 3, 17F, and 19A became predominant late post-PCV10 without a significant increase in serotype-specific IPD incidence compared to pre-PCV10. ConclusionSignificant declines in IPD, including among adults not eligible for vaccination, suggest direct and indirect protection up to nine years after PCV10 introduction, without evidence of significant replacement disease. Continued surveillance is needed to monitor changes in non-vaccine serotypes and inform decisions about introducing higher valent PCVs.

Effectiveness of ten-valent pneumococcal conjugate vaccine on invasive pneumococcal disease among children

The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in March 2015 in Bangladesh. In this study, we aimed to estimate the impact of PCV10 on invasive pneumococcal disease (IPD) identified by blood cultures and severe pneumonia identified clinically and its effectiveness on invasive disease caused by vaccine serotypes.We conducted population-based surveillance among children aged 2- <24 months between April 2012 through March 2019 in Mirzapur, a rural sub-district of Bangladesh. We compared incidence of IPD and severe pneumonia before (April 2012 to March 2015) and after (April 2015 to March 2019) the introduction of PCV10. Vaccine effectiveness was measured using an indirect cohort analysis of data from four sentinel sites in which PCV10 vaccination status was compared between children with IPD caused by vaccine serotype vs. non-vaccine serotypes.We identified 24 IPD cases by blood culture and 1,704 severe pneumonia hospitalizations during the surveillance period. IPD incidence in under-2-year-old children fell 25 % (95 % CI: −1.2 % to 76 %; p-value = 0.59) from 106 cases per 100,000 child-years at baseline to 79.3 in April 2018- March 2019. Vaccine serotype-IPD incidence was lower (77 % reduction, 95 % CI: −0.45 % to 96 %; p-value = 0.068) in April 2018 - March 2019 than in the pre-vaccine period (85.7 cases to 19.8/100,000 child-years). A significant decline of 54.0 % (95 % CI: 47.0 % to 59.0 %; p-value < 0.001) was observed in hospitalizations due to severe pneumonia. From indirect cohort analysis, the effectiveness of PCV10 against vaccine serotype IPD was 37 % (95 % CI: −141.0 % to 83.5 %; p = 0.5) after the 1st dose and 63.1 % (95 % CI: −3.3 % to 85.9 %, p = 0.0411) after the 2nd or the 3rd dose.This study demonstrates that PCV10 introduction prevented hospitalizations with severe pneumonia and provided individual protection against vaccine serotypes.

Molecular characterization of Streptococcus pneumoniae causing disease among children in Nigeria during the introduction of PCV10 (GSK).

Streptococcus pneumoniae (pneumococcus) is a leading vaccine-preventable cause of childhood invasive disease. Nigeria has the second highest pneumococcal disease burden globally, with an estimated ~49 000 child deaths caused by pneumococcal infections each year. Ten-valent pneumococcal conjugate vaccine (GSK; PCV10) was introduced in December 2014 in a phased approach. However, few studies have characterized the disease-causing pneumococci from Nigeria. This study assessed the prevalence of serotypes, antibiotic susceptibility and genomic lineages using whole genome sequencing and identified lineages that could potentially escape PCV10 (GSK). We also investigated the potential differences in pneumococcal lineage features between children with and without sickle cell disease. A collection of 192 disease-causing pneumococcal isolates was obtained from Kano (n=189) and Abuja (n=3) states, Nigeria, between 1 January 2014 and 31 May 2018. The majority (99 %, 190/192) of specimens were recovered from children aged 5 years or under. Among them, 37 children had confirmed or traits of sickle cell disease. Our findings identified 25 serotypes expressed by 43 Global Pneumococcal Sequence Clusters (GPSCs) and 85 sequence types (STs). The most common serotypes were 14 (18 %, n=35), 6B (16 %, n=31), 1 (9 %, n=17), 5 (9 %, n=17) and 6A (9 %, n=17); all except serotype 6A are included in PCV10 (GSK). PCV10 (SII; PNEUMOSIL) and PCV13 formulations include serotypes 6A and 19A which would increase the overall coverage from 67 % by PCV10 (GSK) to 78 and 82 %, respectively. The pneumococcal lineages were a mix of globally spreading and unique local lineages. Following the use of PCV10 (GSK), GPSC5 expressing serotype 6A, GPSC10 (19A), GPSC26 (12F and 46) and GPSC627 (9L) are non-vaccine type lineages that could persist and potentially expand under vaccine-selective pressure. Approximately half (52 %, 99/192) of the pneumococcal isolates were resistant to the first-line antibiotic penicillin and 44 % (85/192) were multidrug-resistant. Erythromycin resistance was very low (2 %, 3/192). There was no significant difference in clinical manifestation, serotype prevalence or antibiotic resistance between children with and without traits of or confirmed sickle cell disease. In summary, our findings show that a high percentage of the pneumococcal disease were caused by the serotypes that are covered by currently available vaccines. Given the low prevalence of resistance, macrolide antibiotics, such as erythromycin, should be considered as an option to treat pneumococcal disease in Nigeria. However, appropriate use of macrolide antibiotics should be vigilantly monitored to prevent the potential increase in macrolide resistance.

Effect of different schedules of ten-valent pneumococcal conjugate vaccine on pneumococcal carriage in Vietnamese infants: results from a randomised controlled trial

WHO recommends a three-dose infant pneumococcal conjugate vaccine (PCV) schedule administered as a two-dose primary series with booster (2+1) or a three-dose primary series (3+0). Data on carriage impacts of these and further reduced PCV schedules are needed to inform PCV strategies. Here we evaluate the efficacy against carriage of four different PCV10 schedules. Participants within an open-label, randomised controlled trial in Ho Chi Minh City, Vietnam, were allocated to receive PCV10 in a 3+1 (2,3,4,9 months, n=152), 3+0 (2,3,4 months, n=149), 2+1 (2,4,9.5 months, n=250) or novel two-dose (2,6 months, n=202) schedule, or no infant doses of PCV (two control groups, n=197 and n=199). Nasopharyngeal swabs collected between 2 and 24 months were analysed (blinded) for pneumococcal carriage and serotypes. Trial registration: ClinicalTrials.gov NCT01953510. Pneumococcal carriage prevalence was low (10.6-14.1% for vaccine-type (VT) at 12-24 months in unvaccinated controls). All four PCV10 schedules reduced VT carriage compared with controls (the 2+1 schedule at 12, 18, and 24 months; the 3+1 and two-dose schedules at 18 months; and the 3+0 schedule at 24 months), with maximum reductions of 40.1%-64.5%. There were no differences in VT carriage prevalence at 6 or 9 months comparing three-dose and two-dose primary series, and no differences at 12, 18, or 24 months when comparing schedules with and without a booster dose. In Vietnamese children with a relatively low pneumococcal carriage prevalence, 3+1, 2+1, 3+0 and two-dose PCV10 schedules were effective in reducing VT carriage. There were no discernible differences in the effect on carriage of the WHO-recommended 2+1 and 3+0 schedules during the first two years of life. Together with the previously reported immunogenicity data, this trial suggests that a range of PCV schedules are likely to generate significant direct and indirect protection. NHMRC, BMGF.

Long-term population impact of infant 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in adults in Finland

BackgroundLimited data are available on long-term indirect effects of ten-valent pneumococcal conjugate vaccine (PCV10) programmes. We evaluated changes in invasive pneumococcal disease (IPD) incidence, mortality, and serotype distribution in adults up to 9 years after infant PCV10 introduction. MethodsCulture-confirmed IPD cases ≥18 years (n = 5610; 85% were pneumonia) were identified through national, population-based laboratory surveillance; data were linked with population registry to conduct nationwide follow-up study. In a time-series model, we compared serotype-specific IPD incidence and associated 30-day mortality rates before and after PCV10 by using negative binomial regression models. ResultsDuring pre-PCV10 period (7/2004–6/2010), overall IPD incidence in adults ≥18 years increased yearly by 4.8%. After adjusting for trend and seasonality, the observed PCV10 serotype IPD incidence in 7/2018–6/2019 was 90% (12/100,000 person-years) lower than the expected rate without PCV10 program. Non-PCV10 serotype incidence was 40% (4.4/100,000 person-years) higher than expected; serotypes 3, 19A, 22F, and 6C accounted for most of the rate increase. However, incidence of non-PCV10 IPD levelled off by end of follow-up. The observed-expected incidence rate-ratio (IRR) was 0·7 (95 %CI 0·5–0.8) for all IPD and 0·7 (95 %CI 0·3–1·3) for IPD-associated 30-day mortality. Case-fatality proportion decreased from 11·9% to 10.0% (p < 0.01). In persons ≥65 years, the IRR was 0·7 (95 %CI 0·5–0.95). ConclusionsSignificant indirect effects were seen for vaccine-serotype IPD and for overall IPD in all adult age groups. For non-vaccine IPD, the incidence stabilized 5 years after infant PVC10 program introduction, resulting in a steady state in which non-vaccine IPD accounted for nearly 90% of overall IPD. Substantial pneumococcal disease burden remains in older adults.

Immunogenicity, otitis media, hearing impairment, and nasopharyngeal carriage 6-months after 13-valent or ten-valent booster pneumococcal conjugate vaccines, stratified by mixed priming schedules: PREVIX_COMBO and PREVIX_BOOST randomised controlled trials

Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules. PREVIX_BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX_COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0·35 μg/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849). Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related. Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children. National Health and Medical Research Council (NHMRC).

Effect of childhood vaccination and antibiotic use on pneumococcal populations and genome-wide associations with disease among children in Nepal: an observational study

SummaryBackgroundPneumococcal disease is a leading cause of bacterial pneumonia and invasive bacterial disease among children globally. The reason some strains of pneumococci are more likely to cause disease, and how interventions such as vaccines and antibiotics affect pneumococcal strains is poorly understood. We aimed to identify genetic regions under selective pressure and those associated with disease through the analysis of pneumococcal whole-genome sequences.MethodsWhole-genome sequencing was performed on pneumococcal isolates collected between January, 2005, and May, 2018, in Kathmandu, Nepal, which included programmatic ten-valent pneumococcal conjugate vaccine (PCV10) introduction in 2015. Isolates were from three distinct cohorts: nasopharyngeal swabs of healthy community-based children, nasopharyngeal swabs of children admitted to hospital with pneumonia, and sterile-site cultures from children admitted to hospital. Across these cohorts we examined serotype distribution, antibiotic resistance, strain distribution, and regions of recombination to determine genes that were undergoing diversifying selection. Genome-wide association studies comparing pneumonia and sterile-site isolates with healthy carriage were used to determine novel variants associated with disease.FindingsAfter programmatic introduction of PCV10, there was a decline in vaccine covered serotypes; however, strains that had expressed these serotypes continued to exist in the post-PCV population. We identified GPSC9 to be a strain of concern due to its high prevalence in disease, multidrug resistance, and ability to switch to an unencapsulated phenotype via insertion of virulence factor pspC into the cps locus. Antibiotic resistance loci to co-trimoxazole were found to be prevalent (pre-PCV10 78% vs post-PCV10 81%; p=0·27) and increasingly prevalent to penicillin (pre-PCV10 15% vs post-PCV10 32%; p<0·0001). Regions with multiple recombinations were identified spanning the surface protein virulence factors pspA and pspC and antibiotic targets pbpX, folA, folC, folE, and folP. Furthermore, we identified variants in lacE2 to be strongly associated with isolates from children with pneumonia and PRIP to be strongly associated with isolates from sterile sites.InterpretationOur work highlights the effect of pneumococcal conjugate vaccines, antibiotics, and host–pathogen interaction in pneumococcal variation, and the pathogen's capability of adapting to these factors at both population-wide and strain-specific levels. Ongoing surveillance of disease-associated strains and further investigation of lacE2 and PRIP as serotype-independent targets for therapeutic interventions is required.FundingGavi, The Vaccine Alliance; WHO; Bill & Melinda Gates Foundation; Wellcome Sanger Institute; and US Centers for Disease Control and Prevention.

Serotype-specific effectiveness against pneumococcal carriage and serotype replacement after ten-valent Pneumococcal Conjugate Vaccine (PCV10) introduction in Pakistan.

ObjectivePakistan was one of the first South-Asian countries to introduce the ten-valent pneumococcal conjugate vaccine (PCV10) at the national level, using a 3+0 schedule without catchup, in 2013.MethodsFrom 2014–18, fifteen children <2 years old were recruited every week in Matiari, Sindh, and nasopharyngeal swabs were collected. The samples were cultured, and pneumococcus was further serotyped through multiplex PCR at the Aga Khan University Hospital as per the method described by the Centers for Disease Control and Prevention, USA.ResultsPneumococcus was detected in 2370/3140 (75%) children. Vaccine type (VT) and non-vaccine type (NVT) serotypes were carried by 379 and 1990 children. There was a significant decline in VT carriage (by 40.3%, p-value <0.001), whereas overall NVT carriage remained the same. The prevalence of VT serotypes 6B, 9V/9A, and 19F showed a significant decline by 58.8%, 79.3%, and 56%, respectively. The prevalence of NVT serotypes 19A, 21, and 10A increased by 70%, 33.3%, and 65.6%, respectively, whereas serotypes 13 and 9N/9L decreased by 53.4% and 51.8%, respectively. Serotype-specific vaccine effectiveness estimates that reached statistical significance were for 9V/9A (VE = 65.0, 95% CI 26.0–83.5%), 19F (VE = 55.3, 95% CI 15.5–76.4%) and for the vaccine related serotype 6A (VE = 28.4, 95% CI 0.9–48.2%).ConclusionThe emergence of NVT serotypes, primarily 19A replacing VT serotypes in this rural community, necessitates continuous monitoring of serotypes in the carriage and invasive disease to evaluate the utility of existing vaccine formulations.

Effect of Different Schedules of Ten-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in Vietnamese Infants: Results From a Randomised Controlled Trial

Effect of Different Schedules of Ten-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in Vietnamese Infants: Results From a Randomised Controlled Trial

Salivary antibody responses to ten-valent pneumococcal conjugate vaccination following two different immunization schedules in a healthy birth cohort

Pneumococcal conjugate vaccines reduce pneumococcal colonization via serotype-specific immunoglobulin G (IgG) at mucosal surfaces. The infant immunization schedule with the ten-valent pneumococcal conjugate vaccine (PCV10) changed from a 3 + 1 schedule (2–3-4–11 months) to a 2 + 1 schedule (2–4–11 months) in The Netherlands in 2013. We compared anti-pneumococcal IgG concentrations in saliva between the schedules. IgG was measured using a fluorescent bead-based multiplex immunoassay at the ages of 6 (post-primary) and 12 (post-booster) months in 51 infants receiving the 3 + 1 schedule and 68 infants receiving the 2 + 1 schedule. Post-primary IgG geometric mean concentrations (GMCs) were comparable between schedules for all vaccine serotypes. Post-booster IgG GMCs were significantly lower after the 2 + 1 schedule for serotypes 4 (p = 0.035), 7F (p = 0.048) and 23F (p = 0.0056). This study shows small differences in mucosal IgG responses between a 3 + 1 and a 2 + 1 PCV10 schedule. Future studies should establish correlates of protection against pneumococcal colonization for mucosal antibodies.

90Factors associated with pneumococcal carriage in children and adults in Fiji, using four cross-sectional surveys

Abstract Background Pneumococcal disease is preceded by carriage of pneumococci. We describe factors associated with pneumococcal nasopharyngeal carriage in Fiji, using data from annual (2012-2015) cross-sectional surveys, pre- and post-introduction of ten-valent pneumococcal conjugate vaccine (PCV10). Methods Infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and their caregivers participated. Pneumococci were detected using lytA qPCR, with molecular serotyping by microarray. We used logistic regression to determine predictors of carriage and density. Results There were 8,109 participants. Pneumococcal carriage was associated with: years post-PCV10 introduction (global P&amp;lt;0.001), iTaukei ethnicity (aOR 2.74 [95% CI 2.17-3.45] P&amp;lt;0.001); young age (global P&amp;lt;0.001); urban residence (aOR 1.45 [95% CI 1.30-2.57] P&amp;lt;0.001); living with &amp;gt;2 children &amp;lt;5 years (aOR 1.42 [95% CI 1.27-1.59] P&amp;lt;0.001); poverty (aOR 1.44 [95% CI 1.28-1.62] P&amp;lt;0.001); and upper respiratory tract infection (URTI) symptoms (aOR 1.77 [95% CI 1.57-2.01] P&amp;lt;0.001). Factors associated with PCV10 and non-PCV10 carriage were similar to those associated with overall carriage. Additionally, PCV10 carriage was associated with PCV10 vaccination (0.58 [95% CI 0.41-0.82] P=0.002) and cigarette smoke exposure (aOR 1.21 [95% CI 1.02-1.43] P=0.031. Non-PCV10 carriage was not associated with years post-PCV10 introduction. Conclusions Introduction of PCV10 reduced the odds of overall and PCV10 pneumococcal carriage in Fiji. ITaukei ethnicity was positively associated with carriage after adjustment for PCV10. Key messages PCV10 introduction was associated with reduced odds of overall and PCV10 pneumococcal carriage in Fiji. Despite high and similar PCV10 coverage rates, iTaukei ethnicity is positively associated with pneumococcal carriage, compared with Fijian of Indian Descent populations.

Impact of national introduction of ten-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in Bangladesh: Case-control and time-trend studies

BackgroundBangladesh introduced the ten-valent pneumococcal conjugate vaccine (PCV10) into its national immunization program in March 2015 creating an opportunity to assess the real-world impact of PCV on invasive pneumococcal disease (IPD). MethodsBetween January 2014 and June 2018, children aged 3–35 months in three rural sub-districts of Sylhet district of Bangladesh were visited every two months to collect morbidity and care-seeking data. Children attending sub-district hospitals with pneumonia, meningitis, or sepsis were assessed for IPD after obtaining informed consent. Blood and cerebrospinal fluid were collected from enrolled children to isolate pneumococcus using culture and molecular test. Children who were age-eligible to receive the PCV and had pneumococcus isolated were enrolled as cases. Four age and sex-matched clinic and community controls were selected for each case within one to two weeks of case identification. Data on immunization status and confounders were collected. PCV coverage was estimated using vaccine coverage surveys. Case-control and incidence trend analyses were conducted to assess the impact of PCV on IPD. ResultsThe community cohort yielded 217,605 child years of observations and 154,773 sick child-visits to study hospitals. Pneumococcus was isolated from 44 children who were age-eligible to receive PCV; these children were enrolled as cases. The cases were matched with 166 community- and 150 clinic-controls. The matched case-control analyses using community-controls showed 83% effectiveness (95% CI: 1.57–97.1%) and clinic controls showed 90% effectiveness (95% CI: −26.0% to 99.1%) of PCV in preventing IPD. Incidence trend analysis estimated vaccine effectiveness at 80.1% (95% CI: 38.4, 93.6). ConclusionPCV in this pediatric population in Bangladesh was highly effective in preventing IPD.

Immunogenicity of alternative ten-valent pneumococcal conjugate vaccine schedules in infants in Ho Chi Minh City, Vietnam: results from a single-blind, parallel-group, open-label, randomised, controlled trial

SummaryBackgroundData are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam.MethodsIn this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9·5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3–18 months depending on group allocation, within 27–43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0·35 μg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual.FindingsBetween Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A–D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84·6% [95% CI 79·9–88·6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76·8% [70·9–82·0] of infants after two doses [group C]; risk difference 7·8% [90% CI 2·1–13·6]) and 23F (90·6% [95% CI 86·6–93·7] vs 77·6% [71·8–82·2]; 12·9% [90% CI 7·7–18·3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F.InterpretationA two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life.FundingAustralian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.

Long-term population effects of infant 10-valent pneumococcal conjugate vaccination on pneumococcal meningitis in Finland

BackgroundNo previous studies have reported long-term follow-up of ten-valent pneumococcal conjugate vaccine (PCV10) program impact on pneumococcal meningitis (PM). We assessed the effects of infant PCV10 program on PM incidence, mortality and serotype distribution in children and adults during 7 years after introduction. MethodsWe conducted a population-based observational study. A case of PM was defined as isolation of Streptococcus pneumoniae from cerebrospinal fluid or, a patient with S. pneumoniae isolated from blood and an ICD-10 hospital discharge diagnosis of bacterial meningitis within 30 days before or after positive culture date.We compared age- and serotype-specific incidence and associated 30-day mortality rates in 2011–2017 (PCV10 period) with those in 2004–2010 (pre-PCV10 baseline) by using Poisson regression models. Absolute rate differences and 95% confidence intervals (CIs) were calculated from the parameter estimates by using delta method. ResultsDuring the PCV10 period, the overall incidence of PCV10 serotype meningitis decreased by 68% (95%CI 57%-77%), and the overall PM incidence by 27% (95%CI: 12%-39%). In age groups 0–4, 50–64, and ≥ 18 years, the overall PM incidence was reduced by 64%, 34% and 19%, respectively. In adults ≥ 65 years of age, a 69% reduction in PCV10 serotypes was offset by 157% (56%-342%) increase in non-PCV10 serotypes. The overall PM-related mortality rate decreased by 42% (95%CI 4%-65%). Overall case fatality proportion (CFP) was 16% in pre-PCV10 period and 12% in PCV10 period (p = 0.41); among persons 50–64 years the CFP decreased from 25% to 10% (p = 0.04). ConclusionsWe observed substantial impact and herd protection for vaccine-serotype PM and associated mortality after infant PCV10 introduction. However, in older adults ≥ 65 years of age, PM burden remains unchanged due to serotype replacement.

Effect of a 2+1 schedule of ten-valent versus 13-valent pneumococcal conjugate vaccine on pneumococcal carriage: Results from a randomised controlled trial in Vietnam

BackgroundPneumococcal conjugate vaccines (PCVs) generate herd protection by reducing nasopharyngeal (NP) carriage. Two PCVs, PCV10 and PCV13, have been in use for over a decade, yet there are few data comparing their impact on carriage. Here we report their effect on carriage in a 2+1 schedule, compared with each other and with unvaccinated controls. MethodsData from four groups within a parallel, open-label randomised controlled trial in Ho Chi Minh City contribute to this article. Three groups were randomised to receive a 2+1 schedule of PCV10 (n = 250), a 2+1 schedule of PCV13 (n = 251), or two doses of PCV10 at 18 and 24 months (controls, n = 197). An additional group (n = 199) was recruited at 18 months to serve as controls from 18 to 24 months. NP swabs collected at 2, 6, 9, 12, 18, and 24 months were analysed (blinded) for pneumococcal carriage. This study aimed to determine if PCV10 and PCV13 have a differential effect on pneumococcal carriage, a secondary outcome of the trial. We also describe the serotype distribution among unvaccinated participants. Trial registration: ClinicalTrials.gov NCT01953510. FindingsCompared with unvaccinated controls, a 2+1 schedule of PCV10 reduced PCV10-type carriage by 45–62% from pre-booster through to 24 months of age, and a 2+1 schedule of PCV13 reduced PCV13-type carriage by 36–49% at 12 and 18 months of age. Compared directly with each other, there were few differences between the vaccines in their impact on carriage. Vaccine serotypes accounted for the majority of carriage in unvaccinated participants. InterpretationBoth PCV10 and PCV13 reduce the carriage of pneumococcal vaccine serotypes. The introduction of either vaccine would have the potential to generate significant herd protection in this population. FundingNational Health and Medical Research Council of Australia, Bill & Melinda Gates Foundation.

An affordable pneumococcal conjugate vaccine after 20 years

An affordable pneumococcal conjugate vaccine after 20 years

Immunogenicity and safety of a novel ten-valent pneumococcal conjugate vaccine in healthy infants in The Gambia: a phase 3, randomised, double-blind, non-inferiority trial

Immunogenicity and safety of a novel ten-valent pneumococcal conjugate vaccine in healthy infants in The Gambia: a phase 3, randomised, double-blind, non-inferiority trial

Impact of National Introduction of Ten-Valent Pneumococcal Conjugate Vaccine on Invasive Pneumococcal Diseases in Bangladesh: Case-Control and Time-Trend Studies

Background: Bangladesh introduced the ten-valent pneumococcal conjugate vaccine (PCV10) in its national immunization program on March 2015 creating an opportunity to assess the real-world impact of PCV on invasive pneumococcal diseases (IPD). Methods: Between January 2014 and June 2018, children aged 3-35 months in Sylhet district of Bangladesh were visited every two months to collect morbidity and care-seeking data. Children attending sub-district hospitals with pneumonia, meningitis, or sepsis were assessed for IPD after obtaining informed consent. Blood and cerebrospinal fluid were collected from enrolled children to isolate pneumococcus using culture and molecular tests. Vaccine-eligible children with pneumococcus isolated were enrolled as cases. Four age and sex-matched clinic and community controls were selected for each case within two weeks of case identification. Data on immunization status and confounders were collected. PCV coverage was estimated using vaccine coverage surveys. Case-control and incidence trend analyses were conducted to assess the impact of PCV on IPD. Results: The community cohort yielded 217,605 child years of observations and 46,013 child-visits to study hospitals. Pneumococcus was isolated from 44 children who were age-eligible to receive PCV; these children were enrolled as cases. The cases were matched with 166 community- and 150 clinic-controls. The matched case-control analyses using community-controls showed 83% effectiveness (95% CI: 1.57% to 97.1%) and clinic controls showed 90% effectiveness (95% CI: -26.0% to 99.1%) in preventing IPD. Incidence trend analysis estimated vaccine effectiveness at 80.1% (95% CI: 38.4, 93.6). Conclusion: PCV in this pediatric population in Bangladesh was highly effective in preventing IPD. Funding Information: This study was funded by the Bill & Melinda Gates Foundation [OPP1084286, OPP1117483] and GlaxoSmithKline [90063241]. Declaration of Interests: None to declare. Ethics Approval Statement: The protocol was approved by the institutional review board of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) in Dhaka, Bangladesh (PR-13095) and the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, USA (IR5421).

Impact and effectiveness of a conjugate vaccine against invasive pneumococcal disease in Finland - a modelling approach

ABSTRACT The evaluation of the public health impact of a vaccination program is essential in monitoring its policy relevance. Vaccine impact (VI) is usually assessed in a before-after design, in which data on disease burden without vaccination program is required from a historical reference period. It takes into account the indirect effects and therefore aims to describe the public health performance of the vaccination program in the population. Vaccine effectiveness (VE), measured in parallel settings, quantifies the benefit for an individual of being vaccinated but does not address the indirect effects of a vaccination program. The motivation of this paper is to gain insight into patterns of how VI and VE have manifested under large-scale use of a ten-valent pneumococcal conjugate vaccine in Finnish children. We construct a simple pseudo-dynamic model that mimics typical post-vaccination trends in the incidences of pneumococcal carriage and invasive disease in children when the proportion of vaccine-type carriage decreases. In the context of the model, we define the parameters of interest for VI and VE and explore how their expected values evolve over time. For comparison, we demonstrate the application of VI and VE estimation by using register data.

Effect of ten-valent pneumococcal conjugate vaccine introduction on pneumonia hospital admissions in Fiji: a time-series analysis

In October, 2012, Fiji introduced routine infant immunisation with a ten-valent pneumococcal conjugate vaccine (PCV10) using three primary doses and no booster dose (3 + 0 schedule). Data are scarce for the effect of PCV in the Asia and Pacific region. We aimed to evaluate the effect of PCV10 on pneumonia hospital admissions in children younger than 5 years and adults aged 55 years and older in Fiji, 5 years after vaccine introduction. We did a time-series analysis assessing changes in pneumonia hospital admissions at three public tertiary hospitals in Fiji. Four pneumonia outcomes were evaluated: all-cause pneumonia, severe or very severe pneumonia, hypoxic pneumonia, and radiological pneumonia. Participants aged younger than 2 months, 2-23 months, 24-59 months, and 55 years and older were included. Data were extracted from the national hospital admission database according to International Classification of Diseases-tenth revision codes J10·0-18·9, J21, and J22 for all-cause pneumonia. Medical records and chest radiographs were reviewed for the main tertiary hospital to reclassify hospital admissions in children aged younger than 2 years as severe or very severe, hypoxic, or radiological pneumonia as per WHO definitions. Time-series analyses were done using the synthetic control method and multiple imputation to adjust for changes in hospital usage and missing data. Between Jan 1, 2007, and Dec 31, 2017, the ratio of observed cases to expected cases for all-cause pneumonia was 0·92 (95% CI 0·70-1·36) for children aged younger than 2 months, 0·86 (0·74-1·00) for children aged 2-23 months, 0·74 (0·62-0·87) for children aged 24-59 months, and 1·90 (1·53-2·31) in adults aged 55 years and older, 5 years after PCV10 introduction. These findings indicate a reduction in all-cause pneumonia among children aged 24-59 months and an increase in adults aged 55 years and older, but no change among children aged younger than 2 months. Among children aged 2-23 months, we observed declines of 21% (95% CI 5-35) for severe or very severe pneumonia, 46% (33-56) for hypoxic pneumonia, and 25% (9-38) for radiological pneumonia. Mortality reduced by 39% (95% CI 5-62) for all-cause pneumonia, bronchiolitis, and asthma admissions in children aged 2-23 months. The introduction of PCV10 was associated with a decrease in pneumonia hospital admissions in children aged 2-59 months. This is the first study in a middle-income country in the Asia and Pacific region to show the effect of PCV on pneumonia, filling gaps in the literature on the effects of PCV10 and 3 + 0 schedules. These data support decision making on PCV introduction for other low-income and middle-income countries in the region. Department of Foreign Affairs and Trade of the Australian Government.