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Background Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Methods Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Findings Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Interpretation Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. Funding UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

Background Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding UK Vaccine Taskforce and National Institute for Health and Care Research.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibodies, effectively reducing vaccine-serotype carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty surrrounding correlate of protection (CoP) estimates and with persistent vaccine-serotype carriage and vaccine-serotype IPD after PCV13 introduction, we aimed to profile population-level immunogenicity among children younger than 5 years in Blantyre, Malawi. METHODS: For this serosurveillance study, we used a random subset of samples from a prospective population-based serosurvey in Blantyre, Malawi, done between Dec 16, 2016, and June 27, 2018. Sample selection was based on age category optimisation among children younger than 5 years, adequate sample volume, and available budget. We measured serotype-specific IgGs against the 13 vaccine serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) and two non-vaccine serotypes (12F and 33F), as well as IgGs against three pneumococcal proteins (PsaA, NanA, and Ply), using ELISA and a direct-binding electrochemiluminescence-based multiplex assay. We estimated population-level, serotype-specific immunogenicity profiles using a linear spline regression model. Analyses included samples stratified to 20 3-month age strata (eg, age

Background: \ud \ud Invasive pneumococcal disease (IPD) in young infants is uncommon but associated with high morbidity and mortality. Accurate data on the burden of IPD in young infants in low-income countries are lacking. We examined the burden of IPD in infants

There are concerns that pneumococcal conjugate vaccines (PCVs) in sub-Saharan Africa sub-optimally interrupt Streptococcus pneumoniae vaccine-serotype (VT) carriage and transmission. Here we assess PCV carriage using rolling, prospective nasopharyngeal carriage surveys between 2015 and 2018, 3.6–7.1 years after Malawi’s 2011 PCV13 introduction. Carriage decay rate is analysed using non-linear regression. Despite evidence of reduction in VT carriage over the study period, there is high persistent residual carriage. This includes among PCV-vaccinated children 3–5-year-old (16.1% relative reduction from 19.9% to 16.7%); PCV-unvaccinated children 6–8-year-old (40.5% reduction from 26.4% to 15.7%); HIV-infected adults 18-40-years-old on antiretroviral therapy (41.4% reduction from 15.2% to 8.9%). VT carriage prevalence half-life is similar among PCV-vaccinated and PCV-unvaccinated children (3.26 and 3.34 years, respectively). Compared with high-income settings, there is high residual VT carriage 3.6–7.1 years after PCV introduction. Rigorous evaluation of strategies to augment vaccine-induced control of carriage, including alternative schedules and catch-up campaigns, is required., Impact of pneumococcal conjugate vaccines (PCV) in controlling carriage needs to be evaluated to inform vaccine policy. Here, Swarthout et al. show in a prospective rolling cross-sectional study in Malawi a high residual prevalence of vaccine-serotype S. pneumoniae 7 years after PCV introduction.

BACKGROUND\ud COVID-19 pandemic has disrupted health services, including vaccination demand. We describe the impact of the COVID-19 pandemic on routine pediatric vaccination in Brazil.\ud METHODS\ud We conducted a retrospective analysis of all vaccine doses provided to children aged 0-6 years from January 2019 to December 2020. We obtained data stratified by age group (0 to 2 years and >2 to 6 years) and Brazilian region. Difference-in-difference (DiD) analyses were performed to compare vaccine uptake in the pre-pandemic (January-February), stay-at-home (March-June), and reopening (July-December) periods.\ud RESULTS\ud The number of vaccine doses administered declined in the stay-at-home period. For children aged 0 to 2 years, the highest reductions were recorded in the North (-25.3%), Northeast (-16.8%) and Central-West (-10.2%) regions. For children aged >2 to 6 years, the highest decline was observed in the North (DiD = -27.2%) and South (DiD = -14.0%) regions. The number of vaccine doses administered in the reopening period has slightly increased in all regions.\ud CONCLUSIONS\ud Vaccination decreased during the COVID-19 pandemic. Although the number of doses recovered in part during the reopening phase, additional strategies, such as increased public awareness and vaccination booster campaigns are required.

Background:\ud The novel coronavirus disease (COVID-19) vaccines may help control the current pandemic but would require immunization levels that would achieve herd immunity. This study aimed to quantify current COVID-19 vaccine acceptance rates, as well as characterize the determinants, enablers and barriers to vaccine acceptability across the globe by synthesizing published evidence.\ud \ud Methods:\ud A systematic review and meta-analysis of studies was performed on studies assessing the acceptability of a COVID-19 vaccine published between November 1st, 2019, and November 30th, 2020. PubMed, Embase and Cochrane central were searched for eligible studies. Data extracted from retained studies was analyzed using STATA statistical software. A quantitative and narrative synthesis was produced.\ud \ud Results:\ud A total of 35 eligible articles (38 studies) involving a total of 70,997 participants across 7 regions and 35 countries were included. All studies were cross-sectional survey designs. The pooled vaccine acceptance rate across 32 studies was 71% (95% CI: 66 – 76%, p2= 99.4%, range: 29-97%). The pooled vaccine acceptance rate of parents for their children across 4 studies was 52% (95% CI: 37-67%, p2= 99.1%). Vaccine uptake was significantly higher among males (N=13 studies), older age groups (N=7), and healthcare providers (N=2). Enablers of vaccine uptake included perceived individual susceptibility to COVID-19 infection (N=11), prior influenza vaccination (N=7) and high vaccine effectiveness (N=6). The most common barriers to vaccine uptake were general negative attitudes towards vaccines/vaccine hesitancy (N=8), concerns over vaccine safety and efficacy (N=6), vaccine side effects (N=5), and misinformation or conspiracy beliefs around the experimental COVID-19 vaccines (N=2).\ud \ud Conclusions:\ud There is a good acceptance of COVID-19 vaccines globally despite wide variations across countries. Public health campaigns may benefit from capitalising on identified enablers and dispelling important barriers with regards to vaccine safety.

Background Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Funding UK Vaccine Task Force and National Institute for Health Research.

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions.

BACKGROUND\ud The population impact of pneumococcal conjugate vaccines (PCVs) depends on direct and indirect protection. Following Malawi's introduction of the 13-valent PCV (PCV13) in 2011, we examined its impact on vaccine and non-vaccine serotype invasive pneumococcal disease among vaccine-eligible-age and vaccine-ineligible-age children and adults.\ud \ud METHODS\ud We did a prospective observational time-series analysis and a case-control study. We used data from between Jan 1, 2006, and Dec 31, 2018, from laboratory-based surveillance at a government hospital in Malawi. This period included 6 years before and 7 years after introduction of PCV13. By use of negative-binomial regression, we evaluated secular trend-adjusted incidence rate ratio (IRR) in vaccine serotype and non-vaccine serotype invasive pneumococcal disease before and after introduction of PCV. We compared predicted counterfactual incidence in hypothetical absence of vaccine with empirically observed incidence following vaccine introduction. The case-control study assessed vaccine effectiveness, comparing PCV uptake among cases of vaccine-eligible-age invasive pneumococcal disease versus matched community controls.\ud \ud FINDINGS\ud Surveillance covered 10 281 476 person-years of observation, with 140 498 blood and 63 291 cerebrospinal fluid cultures. A reduction in total (vaccine serotype plus non-vaccine serotype) invasive pneumococcal disease incidence preceded introduction of PCV: 19% (IRR 0·81, 95% CI 0·74 to 0·88, p

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Background\ud Monitoring the impact of vaccine programs is necessary to identify changes in vaccine efficacy. We report the impact of the 12-year rotavirus vaccine program on diarrhea mortality and hospitalizations and their correlation to socioeconomic indicators.\ud \ud Methods\ud this ecological study describes diarrhea hospitalizations and deaths from 2006 to 2018 in Brazil and correlates rotavirus vaccine coverage, hospitalizations and deaths to socioeconomic indicators and social vulnerability index (SVI) by state and region. Hospitalizations, deaths, and vaccine coverage trends were analyzed using Joinpoint regression models. Associations between hospitalizations, mortality and rotavirus vaccination coverage and socioeconomic and SVI indicators were established using Ordinary Least Square regressions.\ud \ud Results\ud Rotavirus vaccine coverage remained stable between 2006 and 2018 (annual percentage changes (APC) [95%CI]: 4.4% [−0.3%, 9.2%]). Diarrhea hospitalization rates decreased 52.5% (−5.7% [−7.5%, −3.8%]), from 68.4 to 32.5 hospitalizations per 10,000 children

ObjectiveAssess characteristics of clinical pneumonia after introduction of pneumococcal conjugate vaccine (PCV), by HIV exposure status, in children hospitalised in a governmental hospital in Malawi.Methods and findingsWe evaluated 1139 children ≤5 years old hospitalised with clinical pneumonia: 101 HIV-exposed, uninfected (HEU) and 1038 HIV-unexposed, uninfected (HUU). Median age was 11 months (IQR 6–20), 59% were male, median mid-upper arm circumference (MUAC) was 14 cm (IQR 13–15) and mean weight-for-height z score was −0.7 (±2.5). The highest Respiratory Index of Severity in Children (RISC) scores were allocated to 10.4% of the overall cohort. Only 45.7% had fever, and 37.2% had at least one danger sign at presentation. The most common clinical features were crackles (54.7%), nasal flaring (53.5%) and lower chest wall indrawing (53.2%). Compared with HUU, HEU children were significantly younger (9 months vs 11 months), with lower mean birth weight (2.8 kg vs 3.0 kg) and MUAC (13.6 cm vs 14.0 cm), had higher prevalence of vomiting (32.7% vs 22.0%), tachypnoea (68.4% vs 49.8%) and highest RISC scores (20.0% vs 9.4%). Five children died (0.4%). However, clinical outcomes were similar for both groups.ConclusionsIn this post-PCV setting where prevalence of HIV and malnutrition is high, children hospitalised fulfilling the WHO Integrated Management of Childhood Illness criteria for clinical pneumonia present with heterogeneous features. These vary by HIV exposure status but this does not influence either the frequency of danger signs or mortality. The poor performance of available severity scores in this population and the absence of more specific diagnostics hinder appropriate antimicrobial stewardship and the rational application of other interventions.

Background\ud \ud Nasopharyngeal colonisation by S. pneumoniae is a prerequisite for invasive pneumococcal infections. Influenza co-infection leads to increased susceptibility to secondary pneumonia and mortality during influenza epidemics. Increased bacterial load and impaired immune responses to pneumococcus caused by influenza play a role in this increased susceptibility. Using an Experimental Human Challenge Model and influenza vaccines, we examined symptoms experienced by healthy adults during nasal co-infection with S. pneumoniae and live attenuated influenza virus.\ud Methods\ud \ud Randomised, blinded administration of Live Attenuated Influenza Vaccine (LAIV) or Tetravalent Inactivated Influenza Vaccine (TIV) either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density of S. pneumoniae was determined from nasal washes. Participants completed a symptom questionnaire from the first intervention until 6 days post second intervention.\ud Results\ud \ud The timing and type of influenza vaccination and presence of S. pneumoniae in the nasopharynx significantly affected symptom reporting. In the study where influenza vaccination preceded bacterial inoculation: nasal symptoms were less common in the LAIV group than the TIV group (OR 0.57, p < 0.01); with colonisation status only affecting the TIV group where more symptoms were reported by colonised participants compared to non-colonised participants following inoculation (n = 12/23 [52.17%] vs n = 13/38 [34.21%], respectively; p < 0.05). In the study where influenza vaccination followed bacterial inoculation: no difference was seen in the symptoms reported between the LAIV and TIV groups following inoculation and subsequent vaccination; and symptoms were unaffected by colonisation status.\ud Conclusion\ud \ud Symptoms experienced during live viral vaccination and bacterial co-infection in the nasopharynx are directly affected by the precedence of the pathogen acquisition. Symptoms were directly affected by nasal pneumococcal colonisation but only when TIV was given prior to bacterial exposure.

Streptococcus pneumoniae is one of the world’s leading bacterial pathogens, responsible for pneumonia, septicaemia and meningitis. Asymptomatic colonisation of the nasopharynx is considered to be a prerequisite for these severe infections, however little is understood about the biological changes that permit the pneumococcus to switch from asymptomatic coloniser to invasive pathogen. A phase variable type I restriction-modification (R-M) system (SpnIII) has been linked to a change in capsule expression and to the ability to successfully colonise the murine nasopharynx. Using our laboratory data, we have developed a Markov change model that allows prediction of the expected level of phase variation within a population, and as a result measures when populations deviate from those expected at random. Using this model, we have analysed samples from the Experimental Human Pneumococcal Carriage (EHPC) project. Here we show, through mathematical modelling, that the patterns of dominant SpnIII alleles expressed in the human nasopharynx are significantly different than those predicted by stochastic switching alone. Our inter-disciplinary work demonstrates that the expression of alternative methylation patterns should be an important consideration in studies of pneumococcal colonisation.

IntroductionHepatitis E virus (HEV) is a leading cause of acute viral hepatitis in the developing world and is a public health problem, in particular among pregnant women, where it may lead to severe or fatal complications. A recombinant HEV vaccine, 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China), is licensed in China, but WHO calls for further studies to evaluate the safety and immunogenicity of this vaccine in vulnerable populations, and to evaluate protection in pregnancy. We are therefore conducting a phase IV trial to assess the effectiveness, safety and immunogenicity of the HEV 239 vaccine when given in women of childbearing age in rural Bangladesh, where HEV infection is endemic.Methods and analysisEnrolment of a target of approximately 20 000 non-pregnant women, aged 16–39 years, started on 2 October 2017 in Matlab, Bangladesh. Sixty-seven villages were randomised by village at a 1:1 ratio to receive either the HEV vaccine or the control vaccine (hepatitis B vaccine). A 3-dose vaccination series at 0, 1 and 6 months is ongoing, and women are followed up for 24 months. The primary outcome is confirmed HEV disease among pregnant women. After vaccination, participants are requested to report information about clinical hepatitis symptoms. Participants who become pregnant are visited at their homes every 2 weeks to collect information about pregnancy outcome and to screen for clinical hepatitis. All suspected hepatitis cases undergo laboratory testing for diagnostic evaluation. The incidence of confirmed HEV disease among pregnant and non-pregnant women will be compared between the HEV vaccinated and control groups, safety and immunogenicity of the vaccine will also be evaluated.Ethics and disseminationThe protocol was reviewed and approved by the International Centre for Diarrhoeal Disease Research, Bangladesh Research Review Committee and Ethical Review Committee, and the Directorate General of Drug Administration in Bangladesh, and by the Regional Ethics Committee in Norway. This article is based on the protocol version 2.2 dated 29 June 2017. We will present the results through peer-reviewed publications and at international conferences.Trial registration numberThe trial is registered at clinicaltrials.gov with the registry name “Effectiveness Trial to Evaluate Protection of Pregnant Women by Hepatitis E Vaccine in Bangladesh” and the identifierNCT02759991.

Rotavirus vaccines created the opportunity to control diarrhea in children. We describe the rotavirus genotypes before and after the rotavirus vaccine introduction in Brazil.We reviewed the distribution of rotavirus genotypes in Brazil before and after vaccine introduction by searching publication.Eighty-six studies reported 6884 (15.2%) rotavirus episodes among 45,305 children. Rotavirus caused 22.4% and 11.6% of cases before and after vaccine introduction. G1P[8], G9P[8] and G2P[4] heterotypic strains were most common before and after vaccine introduction.The vaccines may have selected heterotypic strains in this highly vaccinated population.

Streptococcus pneumoniae is the main bacterial pathogen involved in pneumonia. Pneumococcal acquisition and colonization density is probably affected by viral co-infections, the local microbiome composition and mucosal immunity. Here, we report the interactions between live-attenuated influenza vaccine (LAIV), successive pneumococcal challenge, and the healthy adult nasal microbiota and mucosal immunity using an experimental human challenge model. Nasal microbiota profiles at baseline are associated with consecutive pneumococcal carriage outcome (non-carrier, low-dense and high-dense pneumococcal carriage), independent of LAIV co-administration. Corynebacterium/Dolosigranulum-dominated profiles are associated with low-density colonization. Lowest rates of natural viral co-infection at baseline and post-LAIV influenza replication are detected in the low-density carriers. Also, we detected the fewest microbiota perturbations and mucosal cytokine responses in the low-density carriers compared to non-carriers or high-density carriers. These results indicate that the complete respiratory ecosystem affects pneumococcal behaviour following challenge, with low-density carriage representing the most stable ecological state., Using a Streptococcus pneumoniae human challenge model, the authors here show that baseline nasal microbiota profiles are associated with pneumococcal acquisition and density, independent of live-attenuated influenza vaccine (LAIV) administration, and with mucosal cytokine responses to LAIV.

Background\ud Pneumococcal infections are major causes of morbidity and mortality worldwide. We use routine hospital admissions data and time-series modelling analysis to estimate the impact of the seven and thirteen valent pneumococcal conjugate vaccines (PCV7 and PCV13) on hospital admissions due to pneumococcal disease in England.\ud Methods\ud Hospital admissions for pneumococcal meningitis, bacteraemia and pneumonia between January 1, 2003 and December 31, 2015 were identified from the national Hospital Episode Statistics database for all age groups in England. We model the impact of pneumococcal vaccination using interrupted time series analysis. Hospital admissions prior to vaccine introduction were extrapolated to predict the expected number of admissions in the absence of pneumococcal vaccines. Admissions avoided over time were estimated by comparing the fitted interrupted time series and the expected model for no vaccination in a Bayesian framework.\ud Results\ud Overall, there were 43 531 (95% credible interval (CrI): 36 486 – 51 346) fewer hospital admissions due to bacteraemia, meningitis and pneumonia in England during the period from 2006 to 2015 than would have been expected if pneumococcal vaccines had not been implemented, with the majority of hospital admissions avoided due to pneumonia. Among young children reductions in meningitis were more common, while among adults reductions in pneumonia admissions were relatively more important, with no evidence for reduced bacteraemia and meningitis among older adults. We estimated that 981 (95% CrI: 391 – 2 018), 749 (95% CrI: 295 – 1 442) and 1 464 (95% CrI: 793 – 2 522) bacteraemia, meningitis and pneumonia related hospital admissions, respectively, were averted in children

BACKGROUND\ud Human papillomavirus (HPV) infection is common among men who have sex with men (MSM), especially among Human Immunodeficiency Virus (HIV)-infected MSM. The prevalence of HPV among MSM, accounts for the higher incidence of HPV-related cancer observed in this population. It is well known that targeted HPV vaccination is an effective way to prevent HPV infection; an intervention which could be beneficial for a high-risk group such as MSM. The current study aimed to assess the attitudes towards and acceptability of the HPV vaccine among MSM in in Urumqi, China.\ud \ud METHODS\ud A total of 253 HIV-uninfected and 205 HIV-infected MSM (in Urumqi, China participated in the current cross-sectional study. Information on HPV-related knowledge, willingness to be vaccinated as well as demographic data were collected through a self-administered survey. A logistic regression model was applied to determine the predictors of HPV vaccine acceptability among the population.\ud \ud RESULTS\ud The survey results indicated that only 218 (47.6%) of MSM questioned were aware of the term HPV, nevertheless, once awareness was established the prevalence of acceptability of free HPV vaccine was recorded at 96.7% of the total MSM sample. However, HIV-uninfected and HIV-infected MSM demonstrated significantly different attitudes in regard to their acceptability of free HPV vaccination (94.9% vs. 99.0%, p

Known and novel pathogens continue to afflict the world's population, and we deploy existing and new vaccines - the best type of weapon we've got - against them. One consequence is that we are accumulating steadily more experience of both the scientific and the ethical requirements of conducting vaccine trials in people. Good science is itself an ethical requirement, as it is meaningless to apply ethical principles to a scientifically flawed product or plan. Bad science can only be bad ethics. And we have learned that ethical principles are a necessity when we apply the benefits of science to the improving of human health.\ud \ud Recent epidemics have provided opportunities to expand our understanding of this field and of the many components of it that we recognize to be necessary to the ethical assessment of vaccines.

Background:\ud We used data from 4 years of pediatric severe acute respiratory illness (SARI) sentinel surveillance in Blantyre, Malawi, to identify factors associated with clinical severity and coviral clustering.\ud \ud Methods:\ud From January 2011 to December 2014, 2363 children aged 3 months to 14 years presenting to the hospital with SARI were enrolled. Nasopharyngeal aspirates were tested for influenza virus and other respiratory viruses. We assessed risk factors for clinical severity and conducted clustering analysis to identify viral clusters in children with viral codetection.\ud \ud Results:\ud Hospital-attended influenza virus–positive SARI incidence was 2.0 cases per 10 000 children annually; it was highest among children aged

Epidemiological and immunological evidence suggests that some vaccines can reduce all-cause mortality through nonspecific changes made to innate immune cells. Here, we present the first data to describe the nonspecific immunological impact of oral vaccination with live-attenuated Typhi strain Ty21a. We vaccinated healthy adults with Ty21a and assessed aspects of innate and adaptive immunity over the course of 6 months. Changes to monocyte phenotype/function were observed for at least 3 months. Changes to innate and adaptive immune cell cytokine production in response to stimulation with vaccine and unrelated nonvaccine antigens were observed over the 6-month study period. The changes that we have observed could influence susceptibility to infection through altered immune responses mounted to subsequently encountered pathogens. These changes could influence all-cause mortality.

OBJECTIVES\ud A routine review of hepatitis A travel vaccination recommendations was brought forward in June 2017 due to hepatitis A vaccine shortages and a concurrent outbreak in men who have sex with men (MSM). There were three objectives: first, to document the review process for changing the recommendations for the UK travellers in June 2017. Second, to study the impact of these changes on prescribing in general practice in 2017 compared with the previous 5 years. Third, to study any changes in hepatitis A notifications in June-October 2017 compared with the previous 5 years.\ud STUDY DESIGN\ud This is an observational study.\ud METHODS\ud Travel vaccination recommendations for countries with either low-risk (90%) status according to child hepatitis A seroprevalence were not changed. A total of 67 intermediate-risk countries with existing recommendations for most travellers and with new data on rural sanitation levels were shortlisted for the analysis. Data on child hepatitis A seroprevalence, country income status, access to sanitation in rural areas and traveller volumes were obtained. Information about the vaccine supply was obtained from Public Health England. Changes to the existing classification were made through expert consensus, based on countries' hepatitis A seroprevalence, sanitation levels, level of income, volume of travel and hepatitis A traveller cases. Data on the number of combined and monovalent hepatitis A-containing vaccines prescribed in England, 2012-2017, were obtained from the National Health Service Business Service Authorities. The number of monthly prescriptions for January-September 2017 was compared with the mean number of prescriptions for the same month in the previous 5 years (t-test, α = 5%, df = 4). The number of hepatitis A cases notified in June-October 2017 not related to the MSM outbreak was compared with the number of notifications in the same months in previous years.\ud RESULTS\ud A total of 36 countries were downgraded based on good access (80+% of population) to sanitation in rural areas and the intermediate-risk status in terms of child hepatitis A seroprevalence. For these countries, vaccination would only be recommended to travellers staying long term, visiting friends and relatives or staying in areas without good sanitation. There was a significant decline in hepatitis A vaccine prescriptions in June-September 2017, and there was no increase in the number of notifications.\ud CONCLUSIONS\ud Hepatitis A vaccination recommendations for travel were revised in 2017 following a systematic approach to maintain continuity of supply after a hepatitis A vaccine shortage and increased hepatitis A vaccine demand related to a large outbreak. Improved access to good sanitation in rural areas and low seroprevalence estimates among children have led to 36 countries to no longer require vaccination for most travellers. These changes do not seem to have impacted on hepatitis A notifications in England, although further research will be needed to quantify the impact more precisely.

Burden of pneumonia caused by Streptococcus pneumoniae remains high despite the availability of conjugate vaccines. Mucosal immunization targeting the lungs is an attractive alternative for the induction of local immune responses to improve protection against pneumonia. Our group had previously described the development of poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) polymeric nanoparticles (NPs) adsorbed with Pneumococcal surface protein A from clade 4 (PspA4Pro) within L-leucine microcarriers (nanocomposite microparticles-NCMPs) for mucosal delivery targeting the lungs (NP/NCMP PspA4Pro). NP/NCMP PspA4Pro was now used for immunization of mice. Inoculation of this formulation induced anti-PspA4Pro IgG antibodies in serum and lungs. Analysis of binding of serum IgG to intact bacteria showed efficient binding to bacteria expressing PspA from clades 3, 4 and 5 (family 2), but no binding to bacteria expressing PspA from clades 1 and 2 (family 1) was observed. Both mucosal immunization with NP/NCMP PspA4Pro and subcutaneous injection of the protein elicited partial protection against intranasal lethal pneumococcal challenge with a serotype 3 strain expressing PspA from clade 5 (PspA5). Although similar survival levels were observed for mucosal immunization with NP/NCMP PspA4Pro and subcutaneous immunization with purified protein, NP/NCMP PspA4Pro induced earlier control of the infection. Conversely, neither immunization with NP/NCMP PspA4Pro nor subcutaneous immunization with purified protein reduced bacterial burden in the lungs after challenge with a serotype 19F strain expressing PspA from clade 1 (PspA1). Mucosal immunization with NP/NCMP PspA4Pro targeting the lungs is thus able to induce local and systemic antibodies, conferring protection only against a strain expressing PspA from the homologous family 2.

Heterogeneity in host susceptibility is a key determinant of infectious disease dynamics but is rarely accounted for in assessment of disease control measures. Understanding how susceptibility is distributed in populations, and how control measures change this distribution, is integral to predicting the course of epidemics with and without interventions. Using multiple experimental and modeling approaches, we show that rainbow trout have relatively homogeneous susceptibility to infection with infectious hematopoietic necrosis virus and that vaccination increases heterogeneity in susceptibility in a nearly all-or-nothing fashion. In a simple transmission model with an R0 of 2, the highly heterogeneous vaccine protection would cause a 35 percentage-point reduction in outbreak size over an intervention inducing homogenous protection at the same mean level. More broadly, these findings provide validation of methodology that can help to reduce biases in predictions of vaccine impact in natural settings and provide insight into how vaccination shapes population susceptibility., IMPORTANCE Differences among individuals influence transmission and spread of infectious diseases as well as the effectiveness of control measures. Control measures, such as vaccines, may provide leaky protection, protecting all hosts to an identical degree, or all-or-nothing protection, protecting some hosts completely while leaving others completely unprotected. This distinction can have a dramatic influence on disease dynamics, yet this distribution of protection is frequently unaccounted for in epidemiological models and estimates of vaccine efficacy. Here, we apply new methodology to experimentally examine host heterogeneity in susceptibility and mode of vaccine action as distinct components influencing disease outcome. Through multiple experiments and new modeling approaches, we show that the distribution of vaccine effects can be robustly estimated. These results offer new experimental and inferential methodology that can improve predictions of vaccine effectiveness and have broad applicability to human, wildlife, and ecosystem health.

Background: \ud The UK Department of Health recommends annual influenza vaccination for healthcare workers, but uptake remains low. For staff, there is uncertainty about the rationale for vaccination and evidence underpinning the recommendation.\ud \ud Objectives: \ud Clarify the rationale, and evidence-base, for influenza vaccination of healthcare workers from the occupational health, employer, and patient safety perspectives.\ud \ud Design: \ud Systematic appraisal of published systematic reviews\ud \ud Results: \ud The quality of the 11 included reviews was variable; some included exactly the same trials but made conflicting recommendations. Three reviews assessed vaccine effects in healthcare workers and found one trial reporting a vaccine efficacy of 88%. Six reviews assessed vaccine effects in healthy adults and vaccine efficacy was consistent with a median of 62% (95% CI 56 to 67). Two reviews assessed effects on working days lost in healthcare workers (three trials), and three reported effects in healthy adults (four trials). The meta-analyses presented by the most recent reviews do not reach standard levels of statistical significance, but may be misleading as individual trials suggest benefit with wide variation in size of effect.\ud The 2013 Cochrane review reported absolute effects close to zero for laboratory-confirmed influenza, and hospitalization for patients, but excluded data on clinically-suspected influenza and all-cause mortality which had shown potentially important effects in previous editions. A more recent systematic review reports these effects as a 42% reduction in clinically-suspected influenza (95% CI 27 to 54), and a 29% reduction in all-cause mortality (95% CI 15 to 41).\ud \ud Conclusions: \ud The evidence for employer and patient safety benefits of influenza vaccination is not straightforward, and has been interpreted differently by different systematic review authors. Future uptake of influenza vaccination among healthcare workers may benefit from a fully transparent guideline process by a panel representing all relevant stakeholders, which clearly communicates the underlying rationale, evidence-base, and judgements made.

Background The spread of resistance to chloroquine (CQ) led to its withdrawal from use in most countries in sub-Saharan Africa in the 1990s. In Malawi, this withdrawal was followed by a rapid reduction in the frequency of resistance to the point where the drug is now considered to be effective once again, just nine years after its withdrawal. In this report, the polymorphisms of markers associated with CQ-resistance against Plasmodium falciparum isolates from coastal Kenya (Kilifi) were investigated, from 1993, prior to the withdrawal of CQ, to 2006, seven years after its withdrawal. Changes to those that occurred in the dihydrofolate reductase gene (dhfr) that confers resistance to the replacement drug, pyrimethamine/sulphadoxine were also compared. Methods Mutations associated with CQ resistance, at codons 76 of pfcrt, at 86 of pfmdr1, and at codons 51, 59 and 164 of dhfr were analysed using PCR-restriction enzyme methods. In total, 406, 240 and 323 isolates were genotyped for pfcrt-76, pfmdr1-86 and dhfr, respectively. Results From 1993 to 2006, the frequency of the pfcrt-76 mutant significantly decreased from around 95% to 60%, while the frequency of pfmdr1-86 did not decline, remaining around 75%. Though the frequency of dhfr mutants was already high (around 80%) at the start of the study, this frequency increased to above 95% during the study period. Mutation at codon 164 of dhf r was analysed in 2006 samples, and none of them had this mutation. Conclusion In accord with the study in Malawi, a reduction in resistance to CQ following official withdrawal in 1999 was found, but unlike Malawi, the decline of resistance to CQ in Kilifi was much slower. It is estimated that, at current rates of decline, it will take 13 more years for the clinical efficacy of CQ to be restored in Kilifi. In addition, CQ resistance was declining before the drug's official withdrawal, suggesting that, prior to the official ban, the use of CQ had decreased, probably due to its poor clinical effectiveness.

Bluetongue virus (BTV) is an economically important arbovirus of ruminants that is transmitted by Culicoides spp. biting midges. BTV infection of ruminants results in a high viraemia, suggesting that repeated sharing of needles between animals could result in its iatrogenic transmission. Studies defining the risk of iatrogenic transmission of blood-borne pathogens by less invasive routes, such as subcutaneous or intradermal inoculations are rare, even though the sharing of needles is common practice for these inoculation routes in the veterinary sector. Here we demonstrate that BTV can be transmitted by needle sharing during subcutaneous inoculation, despite the absence of visible blood contamination of the needles. The incubation period, measured from sharing of needles, to detection of BTV in the recipient sheep or cattle, was substantially longer than has previously been reported after experimental infection of ruminants by either direct inoculation of virus, or through blood feeding by infected Culicoides. Although such mechanical transmission is most likely rare under field condition, these results are likely to influence future advice given in relation to sharing needles during veterinary vaccination campaigns and will also be of interest for the public health sector considering the risk of pathogen transmission during subcutaneous inoculations with re-used needles.

Suboptimal uptake of the measles, mumps and rubella (MMR) vaccine by certain socioeconomic groups may have contributed to recent large measles outbreaks in the UK. We investigated\ud whether socioeconomic deprivation was associated with MMR vaccine uptake over 16 years. Using immunization data for 72 351 children born between 1995 and 2012 in Liverpool, UK, we\ud examined trends in vaccination uptake. Generalized linear models were constructed to examine the relative effect of socioeconomic deprivation and year of birth on MMR uptake. Uptake of MMR1 by age 24 months ranged between 82·5% in 2003 [95% confidence interval (CI) 81·2–83·7] and 93·4% in 2012 (95% CI 92·7–94·2). Uptake of MMR2 by age 60 months ranged between 65·3% (95% CI 64·4–67·4) in 2006 and 90·3% (95% CI 89·4–91·2) in 2012. In analysis adjusted for year of birth and sex, children in the most deprived communities were at significantly greater risk of not receiving MMR1 [risk ratio (RR) 1·70, 95% CI 1·45–1·99] and\ud MMR2 (RR 1·36, 95% CI 1·22–1·52). Higher unemployment and lower household income were significantly associated with low uptake. Contrary to concerns about lower MMR uptake in\ud affluent families, over 16 years, children from the most socioeconomically deprived communities have consistently had the lowest MMR uptake. Targeted catch-up campaigns and strategies to\ud improve routine immunization uptake in deprived areas are needed to minimize the risk of future measles outbreaks.

Background\ud \ud The existing Bacillus Calmette–Guérin (BCG) vaccination provides partial protection against tuberculosis (TB). The modified vaccinia ankara virus-expressing antigen 85A (MVA85A) aims to boost BCG immunity. We evaluated the animal evidence supporting the testing of MVA85A in humans. \ud \ud Methods\ud \ud Our protocol included in vivo preclinical studies of the MVA85A booster with BCG compared with BCG alone, followed by a TB challenge. We used standard methods for systematic review of animal studies, and summarized mortality, measures of pathology and lung bacterial load. The comprehensive literature search was to September 2014. Two independent investigators assessed eligibility and performed data extraction. We assessed study quality and pooled bacteria load using random effect meta-analysis. \ud \ud Findings\ud \ud We included eight studies in 192 animals. Three experiments were in mice, two in guinea pigs, two in macaques and one in calves. Overall, study quality was low with no randomization, baseline comparability not described and blinding not reported. For animal death (including euthanasia due to severe morbidity), studies were underpowered, and overall no benefit demonstrated. No difference was shown for lung pathology measured on an ordinal scale or bacterial load. The largest mortality trial carried out in macaques had more deaths in the MVA85A vaccine group, and was published after a trial in South Africa had started recruiting children. \ud \ud Conclusions\ud \ud This independent assessment of the animal data does not provide evidence to support efficacy of MVA85A as a BCG booster. More rigorous conduct and reporting of preclinical research are warranted, and we believe the results of studies should be publicly available before embarking on trials in humans, irrespective of the findings.

Effective population-level interventions against Plasmodium falciparum malaria lead to age-shifts, delayed morbidity or rebounds in morbidity and mortality whenever they are deployed in ways that do not permanently interrupt transmission. When long-term intervention programmes target specific age-groups of human hosts, the age-specific morbidity rates ultimately adjust to new steady-states, but it is very difficult to study these rates and the temporal dynamics leading up to them empirically because the changes occur over very long time periods. This study investigates the age and magnitude of age- and time- shifting of incidence induced by either pre-erythrocytic vaccination (PEV) programmes or seasonal malaria chemo-prevention (SMC), using an ensemble of individual-based stochastic simulation models of P. falciparum dynamics. The models made various assumptions about immunity decay, transmission heterogeneity and were parameterized with data on both age-specific infection and disease incidence at different levels of exposure, on the durations of different stages of the parasite life-cycle and on human demography. Effects of transmission intensity, and of levels of access to malaria treatment were considered. While both PEV and SMC programmes are predicted to have overall strongly positive health effects, a shift of morbidity into older children is predicted to be induced by either programme if transmission levels remain static and not reduced by other interventions. Predicted shifting of burden continue into the second decade of the programme. Even if long-term surveillance is maintained it will be difficult to avoid mis-attribution of such long-term changes in age-specific morbidity patterns to other factors. Conversely, short-lived transient changes in incidence measured soon after introduction of a new intervention may give over-positive views of future impacts. Complementary intervention strategies could be designed to specifically protect those age-groups at risk from burden shift.

The remarkable clinical success of Fc-fusion proteins has driven intense investigation for even more potent replacements. Using quality-by-design (QbD) approaches, we generated hexameric-Fc (hexa-Fc), a ~20 nm oligomeric Fc-based scaffold that we here show binds low-affinity inhibitory receptors (FcRL5, FcγRIIb and DC-SIGN) with high avidity and specificity, whilst eliminating significant clinical limitations of monomeric Fc-fusions for vaccine and/or cancer therapies, in particular their poor ability to activate complement. Mass spectroscopy of hexa-Fc reveals high-mannose, low-sialic acid content, suggesting that interactions with these receptors are influenced by the mannose-containing Fc. Molecular dynamics (MD) simulations provides insight into the mechanisms of hexa-Fc interaction with these receptors and reveals an unexpected orientation of high-mannose glycans on the human Fc that provides greater accessibility to potential binding partners. Finally, we show that this biosynthetic nanoparticle can be engineered to enhance interactions with the human neonatal Fc receptor (FcRn) without loss of the oligomeric structure, a crucial modification for these molecules in therapy and/or vaccine strategies where a long plasma half-life is critical.

Highlights • The experimental human carriage (EHPC) inoculum is genetically stable over 35 days. • Documentation of stability further addresses concerns of validity and safety of EHPC. • Confidence in EHPC to safely and reproducibly measure VEcol is key to aiding vaccine licensure., Background Pneumococcal carriage is a reservoir for transmission and a precursor to pneumococcal disease. The experimental human pneumococcal carriage model provides a useful tool to aid vaccine licensure through the measurement of vaccine efficacy against carriage (VEcol). Documentation of the genetic stability of the experimental human pneumococcal carriage model is important to further strengthen confidence in its safety and conclusions, enabling it to further facilitate vaccine licensure through providing evidence of VEcol. Methods 229 isolates were sequenced from 10 volunteers in whom experimental human pneumococcal carriage was established, sampled over a period of 35 days. Multiple isolates from within a single volunteer at a single time provided a deep resolution for detecting variation. HiSeq data from the isolates were mapped against a PacBio reference of the inoculum to call variable sites. Results The observed variation between experimental carriage isolates was minimal with the maximum SNP distance between any isolate and the reference being 3 SNPs. Conclusion The low-level variation described provides evidence for the stability of the experimental human pneumococcal carriage model over 35 days, which can be reliably and confidently used to measure VEcol and aid future progression of pneumococcal vaccination.

Background and Aims\ud \ud Rotavirus causes severe diarrhoea and Brazil introduced the Rotarix G1P[8] vaccine in 2006. We aimed to describe changes in rotavirus incidence and diarrhoea epidemiology before and after vaccine introduction.\ud \ud Methods\ud \ud Design: (i) hospital-based survey of children with diarrhoea (2006–2012); (ii) diarrhea-mortality and hospitalization surveillance (1999–2012).\ud \ud Setting\ud \ud (i) Aracaju and (ii) state and national level.\ud \ud Results\ud \ud 1841 children were enrolled and 231 (12.5%) had rotavirus. Rotavirus was less frequent from January-June than from July-December (9.4% versus 20.9%, p

Malaria-specific antibody-dependent respiratory burst activity from neutrophils is acquired in mice following infection; however, vaccination with a leading vaccine antigen fails to induce this activity., New tools are required to expedite the development of an effective vaccine against the blood-stage infection with the human malaria parasite Plasmodium falciparum. This work describes the assessment of the ADRB assay in a mouse model, characterizing the functional interaction between antimalarial serum antibodies and FcRs upon neutrophils. We describe a reproducible, antigen-specific assay, dependent on functional FcR signaling, and show that ADRB activity is induced equally by IgG1 and IgG2a isotypes and is modulated by blocking FcR function. However, following immunization of mice with the blood-stage vaccine candidate antigen MSP142, no measurable ADRB activity was induced against PEMS and neither was vaccine efficacy modulated against Plasmodium yoelii blood-stage challenge in γ−/− mice compared with WT mice. In contrast, following a primary, nonlethal P. yoelii parasite challenge, serum from vaccinated mice and nonimmunized controls showed anti-PEMS ADRB activity. Upon secondary challenge, nonimmunized γ−/− mice showed a reduced ability to control blood-stage parasitemia compared with immunized γ−/− mice; however, WT mice, depleted of their neutrophils, did not lose their ability to control infection. Thus, whereas neutrophil-induced ADRB against PEMS does not appear to play a role in protection against P. yoelii rodent malaria, induction of ADRB activity after challenge suggests that antigen targets of anti-PEMS ADRB activity remain to be established, as well as further supporting the observation that ADRB activity to P. falciparum arises following repeated natural exposure.

Background:\ud The implementation of strategic immunization plans whose development is informed by available locally-relevant research evidence should improve immunization coverage and prevent disease, disability and death in Africa. In general, health research helps to answer questions, generate the evidence required to guide policy and identify new tools. However, factors that influence the publication of immunization research in Africa are not known. We, therefore, undertook this study to fill this research gap by providing insights into factors associated with childhood immunization research productivity on the continent. We postulated that research productivity influences immunization coverage.\ud \ud Methods:\ud We conducted a bibliometric analysis of childhood immunization research output from Africa, using research articles indexed in PubMed as a surrogate for total research productivity. We used zero-truncated negative binomial regression models to explore the factors associated with research productivity.\ud \ud Results:\ud We identified 1,641 articles on childhood immunization indexed in PubMed between 1974 and 2010 with authors from Africa, which represent only 8.9% of the global output. Five countries (South Africa, Nigeria, The Gambia, Egypt and Kenya) contributed 48% of the articles. After controlling for population and gross domestic product, The Gambia, Guinea-Bissau and Sao Tome and Principe were the most productive countries. In univariable analyses, the country's gross domestic product, total health expenditure, private health expenditure, and research and development expenditure had a significant positive association with increased research productivity. Immunization coverage, adult literacy rate, human development index and physician density had no significant association. In the multivarable model, only private health expenditure maintained significant statistical association with the number of immunization articles.\ud \ud Conclusions:\ud Immunization research productivity in Africa is highly skewed, with private health expenditure having a significant positive association. However, the current contribution of authors from Africa to global childhood immunization research output is minimal. The lack of association between research productivity and immunization coverage may be an indication of lack of interactive communication between health decision-makers, program managers and researchers; to ensure that immunization policies and plans are always informed by the best available evidence.

Background\ud \ud Malawi commenced the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant immunisation schedule in November 2011. Here we have tested the utility of high throughput whole genome sequencing to provide a high-resolution view of pre-vaccine pneumococcal epidemiology and population evolutionary trends to predict potential future change in population structure post introduction.\ud \ud Methods\ud \ud One hundred and twenty seven (127) archived pneumococcal isolates from randomly selected adults and children presenting to the Queen Elizabeth Central Hospital, Blantyre, Malawi underwent whole genome sequencing.\ud \ud Results\ud \ud The pneumococcal population was dominated by serotype 1 (20.5% of invasive isolates) prior to vaccine introduction. PCV13 is likely to protect against 62.9% of all circulating invasive pneumococci (78.3% in under-5-year-olds). Several Pneumococcal Molecular Epidemiology Network (PMEN) clones are now in circulation in Malawi which were previously undetected but the pandemic multidrug resistant PMEN1 lineage was not identified. Genome analysis identified a number of novel sequence types and serotype switching.\ud \ud Conclusions\ud \ud High throughput genome sequencing is now feasible and has the capacity to simultaneously elucidate serotype, sequence type and as well as detailed genetic information. It enables population level characterization, providing a detailed picture of population structure and genome evolution relevant to disease control. Post-vaccine introduction surveillance supported by genome sequencing is essential to providing a comprehensive picture of the impact of PCV13 on pneumococcal population structure and informing future public health interventions.

Objective\ud To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis.\ud \ud Methods\ud Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection.\ud \ud Results\ud 4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson's correlation r = −0.91; p

Background Epidemiological studies suggest that inhalation of carbonaceous particulate matter from biomass combustion increases susceptibility to bacterial pneumonia. In vitro studies report that phagocytosis of carbon black by alveolar macrophages (AM) impairs killing of Streptococcus pneumoniae. We have previously reported high levels of black carbon in AM from biomass smoke-exposed children and adults. We therefore aimed to use a mouse model to test the hypothesis that high levels of carbon loading of AM in vivo increases susceptibility to pneumococcal pneumonia. Methods Female outbred mice were treated with either intranasal phosphate buffered saline (PBS) or ultrafine carbon black (UF-CB in PBS; 500 μg on day 1 and day 4), and then infected with S. pneumoniae strain D39 on day 5. Survival was assessed over 72 h. The effect of UF-CB on AM carbon loading, airway inflammation, and a urinary marker of pulmonary oxidative stress was assessed in uninfected animals. Results Instillation of UF-CB in mice resulted a pattern of AM carbon loading similar to that of biomass-smoke exposed humans. In uninfected animals, UF-CB treated animals had increased urinary 8-oxodG (P = 0.055), and an increased airway neutrophil differential count (P < 0.01). All PBS-treated mice died within 72 h after infection with S. pneumoniae, whereas morbidity and mortality after infection was reduced in UF-CB treated animals (median survival 48 h vs. 30 h, P < 0.001). At 24 hr post-infection, UF-CB treated mice had lower lung and the blood S. pneumoniae colony forming unit counts, and lower airway levels of keratinocyte-derived chemokine/growth-related oncogene (KC/GRO), and interferon gamma. Conclusion Acute high level loading of AM with ultrafine carbon black particles per se does not increase the susceptibility of mice to pneumococcal infection in vivo.

1. Introduction\ud The natural reservoir for Streptococcus pneumoniae (the ‘pneumococcus’) is the human nasopharynx and is believed to be a pre-requisite for mucosal (otitis media and pneumonia) and invasive disease (Bacteraemia and meningitis) [1]. Recent WHO estimates suggest that the pneumococcus is the leading cause of death in the under 5 age groups world-wide, with the majority of these in sub-Saharan Africa and Asia [2]. The dynamics between the nasopharyngeal mucosal immune system and microbial colonisers such as the pneumococcus need to be understood in order to develop reliable markers of vaccine efficacy and protection, and also to correctly formulate mucosal vaccines and/or adjuvants. Due to drawbacks with currently available polysaccharide based vaccines, efforts are underway within the research community to develop a new, possibly inhaled, vaccine(s) that will utilise pneumococcal proteins conserved across different polysaccharide serotypes, together with appropriate adjuvants for application into humans [3]. On a wet Thursday morning the doors of the Liverpool Medical Institute were opened to mark the opening of the workshop attended by 69 delegates from institutions across the UK, Switzerland, Finland, Cyprus, Israel and Malawi. Proceedings commenced inside the auditorium with a welcome note delivered on behalf of the organising committee by Dr Adam Wright (BRC). Dr Wright emphasised the main aim of the day – ‘collaborative discussions’ – hoping that the workshop would provide a stimulus towards the development of new and exciting research collaborations amongst the delegates. Michael Head (Infectious Disease Research Network) subsequently took the lead to highlight the role of the IDRN, specifically the promoting and fostering of new and existing collaborations, and the stimulation of multidisciplinary research. In addition Mr Head thanked the sponsors – GlaxoSmithKline, Wyeth and Sanofi Pasteur – for their financial support in staging the workshop.

Background Cathepsin-like enzymes have been identified as potential targets for drug or vaccine development in many parasites, as their functions appear to be essential in a variety of important biological processes within the host, such as molting, cuticle remodeling, embryogenesis, feeding and immune evasion. Functional analysis of Caenorhabditis elegans cathepsin L (Ce-cpl-1) and cathepsin Z (Ce-cpz-1) has established that both genes are required for early embryogenesis, with Ce-cpl-1 having a role in regulating in part the processing of yolk proteins. Ce-cpz-1 also has an important role during molting. Methods and Findings RNA interference assays have allowed us to verify whether the functions of the orthologous filarial genes in Brugia malayi adult female worms are similar. Treatment of B. malayi adult female worms with Bm-cpl-1, Bm-cpl-5, which belong to group Ia of the filarial cpl gene family, or Bm-cpz-1 dsRNA resulted in decreased numbers of secreted microfilariae in vitro. In addition, analysis of the intrauterine progeny of the Bm-cpl-5 or Bm-cpl Pro dsRNA- and siRNA-treated worms revealed a clear disruption in the process of embryogenesis resulting in structural abnormalities in embryos and a varied differential development of embryonic stages. Conclusions Our studies suggest that these filarial cathepsin-like cysteine proteases are likely to be functional orthologs of the C. elegans genes. This functional conservation may thus allow for a more thorough investigation of their distinct functions and their development as potential drug targets., Author Summary Filarial nematodes are an important group of human pathogens, causing lymphatic filariasis and onchocerciasis, and infecting around 150 million people throughout the tropics with more than 1.5 billion at risk of infection. Control of filariasis currently relies on mass drug administration (MDA) programs using drugs which principally target the microfilarial life-cycle stage. These control programs are facing major challenges, including the absence of a drug with macrofilaricidal or permanent sterilizing activity, and the possibility of the development of drug-resistance against the drugs available. Cysteine proteases are essential enzymes which play important roles in a wide range of cellular processes, and the cathepsin-like cysteine proteases have been identified as potential targets for drug or vaccine development in many parasites. Here we have studied the function of several of the cathepsin-like enzymes in the filarial nematode, B. malayi, and demonstrate that these cysteine proteases are involved in the development of embryos, show similar functions to their counterparts in C. elegans, and therefore, provide an important target for future drug development targeted to eliminate filariasis.

Background\ud \ud Malaria control in Africa is most tractable in urban settlements yet most research has focused on rural settings. Elimination of malaria transmission from urban areas may require larval control strategies that complement adult mosquito control using insecticide-treated nets or houses, particularly where vectors feed outdoors. \ud \ud Methods and Findings\ud \ud Microbial larvicide (Bacillus thuringiensis var. israelensis (Bti)) was applied weekly through programmatic, non-randomized community-based, but vertically managed, delivery systems in urban Dar es Salaam, Tanzania. Continuous, randomized cluster sampling of malaria infection prevalence and non-random programmatic surveillance of entomological inoculation rate (EIR) respectively constituted the primary and secondary outcomes surveyed within a population of approximately 612,000 residents in 15 fully urban wards covering 55 km2. Bti application for one year in 3 of those wards (17 km2 with 128,000 residents) reduced crude annual transmission estimates (Relative EIR [95% Confidence Interval] = 0.683 [0.491-0.952], P = 0.024) but program effectiveness peaked between July and September (Relative EIR [CI] = 0.354 [0.193 to 0.650], P = 0.001) when 45% (9/20) of directly observed transmission events occurred. Larviciding reduced malaria infection risk among children ≤5 years of age (OR [CI] = 0.284 [0.101 to 0.801], P = 0.017) and provided protection at least as good as personal use of an insecticide treated net (OR [CI] = 0.764 [0.614-0.951], P = 0.016). \ud \ud Conclusions\ud \ud In this context, larviciding reduced malaria prevalence and complemented existing protection provided by insecticide-treated nets. Larviciding may represent a useful option for integrated vector management in Africa, particularly in its rapidly growing urban centres.

The report describes successful management of 10 women in 2nd and 3rd pregnancy trimesters with EchiTab IgG antivenom after carpet viper (Echis ocellatus) envenoming. All women survived but foetal loss in a victim with delayed presentation and a case of mild hypersensitivity reaction were recorded. Excellent outcomes can be achieved in rural and semi-nomadic populations without specialized care and immediate access and provision of effective antivenoms is paramount in curtailing snakebite maternal morbidity, mortality and foetal loss.

Background Fasciola hepatica, along with Fasciola gigantica, is the causative agent of fasciolosis, a foodborne zoonotic disease affecting grazing animals and humans worldwide. Pathology is directly related to the release of parasite proteins that facilitate establishment within the host. The dominant components of these excretory-secretory (ES) products are also the most promising vaccine candidates, the cathepsin L (Cat L) protease family. Methodology/Principal Findings The sub-proteome of Cat L proteases from adult F. hepatica ES products derived from in vitro culture and in vivo from ovine host bile were compared by 2-DE. The individual Cat L proteases were identified by tandem mass spectrometry with the support of an in-house translated liver fluke EST database. The study reveals plasticity within the CL1 clade of Cat L proteases; highlighted by the identification of a novel isoform and CL1 sub-clade, resulting in a new Cat L phylogenetic analysis including representatives from other adult Cat L phylogenetic clades. Additionally, for the first time, mass spectrometry was shown to be sufficiently sensitive to reveal single amino acid polymorphisms in a resolved 2-DE protein spot derived from pooled population samples. Conclusions/Significance We have investigated the sub-proteome at the population level of a vaccine target family using the Cat L proteases from F. hepatica as a case study. We have confirmed that F. hepatica exhibits more plasticity in the expression of the secreted CL1 clade of Cat L proteases at the protein level than previously realised. We recommend that superfamily based vaccine discovery programmes should screen parasite populations from different host populations and, if required, different host species via sub-proteomic assay in order to confirm the relative expression at the protein level prior to the vaccine development phase., Author Summary Vaccines for neglected parasitic diseases are of paramount importance. An understanding of the basic biology underpinning target expression within parasite populations is one of the pre-requisites for vaccine discovery and development. Fasciola hepatica causes global disease in humans and their livestock. The pathology of the disease is associated with the release of cathepsin L (Cat L) proteases from the parasite into the host. The Cat L proteases are the leading vaccine candidates and are split into 5 clades with different functions. The CL1 clade has undergone significant divergence resulting in the formation of sub-clades. We have studied this vaccine candidate family at the population level with proteomic based assays using F. hepatica as a case study. We have identified differences in Cat L protein expression profiles between in vitro culture compared to in vivo host bile, with CL1 members showing greater expression plasticity. Selection pressure exerted by the host driving the divergence of the CL1 clade is revealed by single amino acid polymorphisms. This case study highlights that high resolution population based proteomic assays at the vaccine discovery stage will support the successful development of broad population based commercial vaccines based on defined antigens and their families.

Background: Pneumococcal colonisation, although usually asymptomatic, is key to the pathogenesis of invasive disease. Colonisation is infrequently detected in older adults, despite their high rates of pneumococcal disease; this may relate to sampling from the wrong site or reliance on culture-based rather than molecular diagnostic methods. Anti-pneumococcal immunity (including responses to vaccination) declines with age, but the immunogenicity of colonisation in older adults has not been studied. Alongside innate immunity, three specific defence mechanisms exist against pneumococcal disease: herd immunity, adaptive immunity (conferred by natural or vaccine-induced antibodies) and antibiotics. Current pneumococcal vaccines confer incomplete protection against pneumococcal disease in older adults.\ud Research Questions:\ud 1. Can experimental human pneumococcal colonisation be safely established in older adults?\ud 2. What is the rate of experimental colonisation in older adults?\ud 3. Do anti-pneumococcal antibodies (natural or post-vaccination) prevent experimental colonisation in older adults?\ud 4. Is experimental colonisation immunogenic in older adults?\ud 5. What is the optimal sampling site and diagnostic methodology for detecting colonisation in older adults?\ud 6. What do colonisation studies of the general adult population reveal about herd immunity and pneumococcal antimicrobial resistance in the community?\ud Findings: Experimental colonisation was established in 39% of volunteers (n = 25/64) with no adverse events. Experimental colonisation was unaffected by previous pneumococcal polysaccharide vaccination or baseline anti-capsular antibody levels. Although the rate of experimental colonisation was similar to that of younger volunteers in previous studies, the immune responses were markedly different: older adults did not demonstrate serotype-specific immune boosting following pneumococcal colonisation. Furthermore, pneumococcal challenge without colonisation led to a drop in specific antibody levels. Nasal wash culture appeared to be the optimal detection strategy compared with molecular testing of nasal wash, oropharyngeal swab or saliva.\ud In a review of all prospective experimental human pneumococcal colonisation volunteers between 2010 and 2017, community-acquired colonisation was identified at baseline in 6.5% (n = 52/795) using nasal wash culture. The commonest serotype was 3 (a vaccine serotype), but otherwise non-vaccine serotypes predominated. There were no changes in serotype distribution over time. 15% of isolates (n = 8/52, all identified in 2015 or later) were resistant to at least one of the antibiotics tested.\ud Conclusions: Experimental pneumococcal colonisation is feasible and safe in older people. However, the immunological effects are different to those identified in younger adults in previous studies. We found no evidence that the niche of colonisation changes with age. Nasal wash culture detected higher-than-expected rates of community-acquired colonisation in young adults, with the dominance of non-vaccine serotypes suggesting that the limits of herd immunity have been reached. New pneumococcal vaccines are needed for older adults, and the experimental colonisation model could be used in early phase testing of candidate vaccines. If such vaccines continue to rely on serotype-specific protection, then community colonisation studies could inform the serotype composition.

The assessment of naturally-acquired and vaccine-induced immunity to blood-stage Plasmodium falciparum malaria is of long-standing interest. However, the field has suffered from a paucity of in vitro assays that reproducibly measure the anti-parasitic activity induced by antibodies in conjunction with immune cells. Here we optimize the antibody-dependent respiratory burst (ADRB) assay, which assesses the ability of antibodies to activate the release of reactive oxygen species from human neutrophils in response to P. falciparum blood-stage parasites. We focus particularly on assay parameters affecting serum preparation and concentration, and importantly assess reproducibility. Our standardized protocol involves testing each serum sample in singlicate with three independent neutrophil donors, and indexing responses against a standard positive control of pooled hyper-immune Kenyan sera. The protocol can be used to quickly screen large cohorts of samples from individuals enrolled in immuno-epidemiological studies or clinical vaccine trials, and requires only 6 μL of serum per sample. Using a cohort of 86 samples, we show that malaria-exposed individuals induce higher ADRB activity than malaria-naïve individuals. The development of the ADRB assay complements the use of cell-independent assays in blood-stage malaria, such as the assay of growth inhibitory activity, and provides an important standardized cell-based assay in the field.

The burden of pneumococcal pneumonia remains high worldwide. The disease disproportionately affects infants, the elderly and the immunocompromised. Nasopharyngeal colonisation with S. pneumoniae is the pre-requisite for disease but also, paradoxically, an immunising event. Current pneumococcal vaccines offer limited protection against pneumonia and do not offer serotype-independent coverage. Serotype replacement is particularly concerning. Identification of serotype-independent correlates of protection against S. pneumoniae infection will accelerate development of vaccines with broad coverage. Protein vaccines are a particularly promising way to confer serotype-independent protection.\ud The experimental human pneumococcal challenge (EHPC) model enables us to investigate correlates of protection against experimental colonisation with S. pneumoniae and study protein-directed immune responses to nasopharyngeal colonisation with the bacteria. A multiplex Luminex assay was developed and used to measure serum IgG against 75 conserved pneumococcal antigens pre- and post-intranasal inoculation with two serotypes of pneumococcus (6B and 15B) in EHPC volunteers. Peripheral blood mononuclear cells taken pre- and post-challenge with serotype 6B pneumococcus were used to evaluate correlation between protein-specific IgG+ memory B-cell responses and protection against experimental colonisation as well as memory B-cell responses to pneumococcal challenge by ELISpot. Memory B-cell responses to six selected proteins and the novel PnuBioVax vaccine were investigated. The results of this work showed that colonisation with serotype 6B pneumococcus induces significant systemic protein-mediated antibody and memory B-cell responses. No single protein antigen correlated with protection against experimental colonisation with S. pneumoniae. However, whilst not significant, there was a trend that PnuBioVax-specific memory B-cells conferred protection against experimental pneumococcal colonisation. Five novel nanoparticle-based vaccines were also investigated to determine their effects on dendritic cell maturation and support of T-cell activation. One of these nanoparticles was subsequently loaded with pneumococcal protein PspA to investigate antigen-specific response. Further work is needed to ascertain the immune response to these novel vaccines, though they are a promising method of serotype-independent vaccine delivery.\ud It is likely that for a novel pneumococcal protein vaccine to confer serotype-independent protection against pneumococcal pneumonia, a combination of protein antigens will need to be included in vaccine formulations. Mucosal vaccination in particular will likely be needed to induce robust immunity